Quinolone derivative or salt thereof

ABSTRACT

A platelet aggregation inhibitor comprising a quinolone derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a novel quinolone derivative or a pharmaceutically acceptable salt thereof useful as a platelet aggregation inhibitor.

TECHNICAL FIELD

The present invention relates to a platelet aggregation inhibitor and aP2Y12 inhibitor comprising a quinolone derivative or a pharmaceuticallyacceptable salt thereof as an active component, and a novel quinolonederivative or a pharmaceutically acceptable salt thereof useful as apharmaceutical agent, particularly a platelet aggregation inhibitor anda P2Y12 inhibitor.

BACKGROUND OF THE INVENTION

Since platelet was discovered in 1842 by Donne, platelet has beenconsidered as one blood component required for hemostasis for a longtime. Presently, it is demonstrated that platelet not only just plays aprinciple role in the hemostatic mechanism but also exertsmulti-functionality for example in the establishment of arteriosclerosishaving been drawing clinical attention and the involvement incirculatory diseases including thrombotic diseases, cancer metastasis,inflammations, and post-graft rejections, and additionally in immunereactions.

Generally, therapies for blood reperfusion with pharmaceutical agents orphysical methods have been done for thrombotic diseases and ischemicdiseases. However, it has been found in recent years that phenomena suchas the elevation of platelet activation, adhesion and aggregation occurafter blood reperfusion, for example via the rupture of vascular tissuesincluding endothelial cells or the deterioration of the balance betweenfibrinogenolysis and coagulation with pharmaceutical agents themselves.Clinically, such phenomena have drawn attention. It has also beenrevealed that after reperfusion is established with thrombolysis usingfor example t-PA, fibrinolysis potency and coagulation potency areactivated, leading to the deterioration of the balance between systemiccoagulation and fibrinolysis. Clinically, such phenomena inducere-occlusion and cause serious clinical problems (non-patent reference1).

Meanwhile, PTCA and stenting have spread rapidly for the therapeutictreatment of diseases based on the constrictions of coronary artery andaorta, including for example angina and myocardial infarction, to givecertain fruitful results. However, these therapies disadvantageouslydamage vascular tissues including endothelial cells, so that acutecoronary occlusion and restenosis emerging at chronic stage draw seriousconcerns. Platelet plays an important role in various thromboticdisorders (re-occlusion and the like) after blood reperfusion therapy.Therefore, anti-platelet agents efficacious in these cases are nowdesired. However, anti-platelet agents in the related art have not yetbeen verified to be sufficiently effective.

As the prophylactic or therapeutic agents of these circulatory diseases,platelet aggregation inhibitors such as aspirin, indometacin,cilostazol, prostaglandin I₂, prostaglandin E₁, ticlopidine, anddipyridamole have been used. Recently, GPIIb/IIIa antagonists inhibitingthe final stage of platelet aggregation and having a potent plateletaggregation-inhibiting activity has additionally been developed. Theapplication thereof is however limited to intravenous infusion at theacute stage of thrombosis (non-patent reference 2).

It has been elucidated in recent years concerning ticlopidine for use asan anti-platelet agent that an active metabolite thereof can exert itsplatelet aggregation-inhibiting action by inhibiting P2Y12 as an ADPreceptor. Reports have subsequently been issued, tellingtriazolo[4,5-D]pyrimidine derivative (patent reference 1) and piperidineand/or homopiperazine (patent reference 2 and patent reference 3) ascompounds with the P2Y12-inhibiting action.

Anti-microbial compounds represented by the formula (A) have been knownas quinolone derivatives (patent reference 4). However, it has neverbeen known that these derivatives have a platelet aggregation-inhibitingaction.

(See the official gazette of the patent reference 4 about the symbols inthe formula.)

[Non-patent reference 1] Journal of the American College of Cardiology,1988, Vol. 12, p. 616-623

[Non-patent reference 2] General Clinical Practice (“Sogo Rinsho” inJapanese), 2003, Vol. 52, p. 1516-1521

[Patent reference 1] The pamphlet of International Publication WO00/34283

[Patent reference 2] The pamphlet of International Publication WO02/098856

[Patent reference 3] The pamphlet of International Publication WO03/022214

[Patent reference 4] The pamphlet of International Publication WO98/23592

DISCLOSURE OF THE INVENTION

In such circumstances, it is strongly desired to develop ananti-platelet agent with a high safety profile with a smaller adversebleeding effect and with distinct pharmaceutical efficacies.

Thus, it is an object of the invention to provide a platelet aggregationinhibitor and a P2Y12 inhibitor having a high pharmacological effect anda good balance between the pharmacological effect and the safetyprofile, and a novel compound useful as a platelet aggregation inhibitorand a P2Y12 inhibitor having a high pharmacological effect and a goodbalance between the pharmacological effect and the safety profile.

Thus, the invention has been achieved.

The present inventors made investigations so as to overcome theproblems. The inventors found that a quinolone derivative represented bythe following formula (I) or a pharmaceutically acceptable salt thereofis a compound with a novel skeleton and with an excellent plateletaggregation-inhibiting action and a P2Y12-inhibiting action.

Specifically, the invention relates to a platelet aggregation inhibitorcomprising a quinolone derivative represented by the formula (I) or apharmaceutically acceptable salt thereof as the active ingredient:

[the symbols in the formula have the following meanings:

-   -   X: C—R⁷ or N;    -   Y: C—R⁶ or N;    -   R¹¹: —H, a lower alkyl which may be substituted, or an amino        which may be substituted with a lower alkyl which may be        substituted;    -   R¹²: —H, or a lower alkyl or an aryl, which respectively may be        substituted, provided that R¹¹ and R¹² together with the        adjacent nitrogen may form a cyclic amino which may be        substituted;    -   R²: a lower alkyl, a cycloalkyl, an aryl or hetero-ring, which        respectively may be substituted;    -   R³: a halogen, a lower alkyl or —O-lower alkyl;    -   R⁴: a cycloalkyl or a non-aromatic hetero ring, which        respectively may be substituted, or a lower alkyl substituted        with a cycloalkyl; provided that in case that R⁴ represents a        non-aromatic hetero ring which may be substituted, a carbon atom        composing the ring binds to the adjacent NH;    -   R⁵: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower        alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl,        —OH, —NHCO-lower alkyl, —N(a lower alkyl)CO-lower alkyl, an        amino which may be substituted with a lower alkyl, or a cyclic        amino which may be substituted;    -   R⁶: —H, a halogen, a lower alkyl or a halogeno-lower alkyl;    -   R⁷: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl);    -   provided that when Y represents C—R⁶, R² and R⁶ together may        form a lower alkylene or a lower alkenylene.

In accordance with the invention, the following inventions described in(2) through (21) are provided.

(2) A P2Y12 inhibitor comprising the quinolone derivative of the formula(I) or a pharmaceutically acceptable salt thereof as an activeingredient.

(3) Use of the quinolone derivative of the formula (I) or apharmaceutically acceptable salt thereof as a platelet aggregationinhibitor.

(4) Use of the quinolone derivative of the formula (I) or apharmaceutically acceptable salt thereof as a P2Y12 inhibitor.

(5) Use of the quinolone derivative of the formula (I) or apharmaceutically acceptable salt thereof so as to produce a plateletaggregation inhibitor.

(6) Use of the quinolone derivative of the formula (I) or apharmaceutically acceptable salt thereof so as to produce a P2Y12inhibitor.

(7) A novel quinolone derivative represented by the formula (I-a) or apharmaceutically acceptable salt thereof:

[the symbols in the formula have the following meanings:

-   -   X: C—R⁷ or N;    -   Y: C—R⁶ or N;    -   R¹¹: —H, a lower alkyl which may be substituted, or an amino        which may be substituted with a lower alkyl which may be        substituted;    -   R¹²: —H, or a lower alkyl or an aryl, which independently may be        substituted, provided that R¹¹ and R¹² together with the        adjacent nitrogen may form a cyclic amino which may be        substituted;    -   R²: a lower alkyl, a cycloalkyl, an aryl or hetero-ring, which        respectively may be substituted;    -   R³: a halogen, a lower alkyl or —O-lower alkyl;    -   R⁴: a cycloalkyl or a non-aromatic hetero ring, which        respectively may be substituted, or a lower alkyl substituted        with a cycloalkyl; provided that in case that R⁴ represents a        non-aromatic hetero ring which may be substituted, a carbon atom        composing the ring binds to the adjacent NH;    -   R⁵: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower        alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl,        —OH, —NHCO-lower alkyl, —N-a lower alkyl)CO-lower alkyl, an        amino which may be substituted with a lower alkyl, or a cyclic        amino which may be substituted;    -   R⁶: —H, a halogen, a lower alkyl or a halogeno-lower alkyl;    -   R⁷: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl);    -   provided that when Y represents C—R⁶, R² and R⁶ together may        form a lower alkylene or a lower alkenylene and provided that        4-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide        is excluded.

(8) The compound described above in (7), where X is CH.

(9) The compound described above in (8), where R³ is a halogen.

(10) The compound described above in (9), where R⁴ is a cycloalkyl.

(11) The compound described above in (10), where R⁵ is —H, —OH or ahalogen.

(12) The compound described in (11), where R¹² is a lower alkylrespectively substituted with one or more groups selected from the GroupQ (provided that at least one is substituted with a group of the GroupP):

-   -   Group P: —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂; and    -   Group Q: —F, —OH, —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)2

(13) The compound described in (11), wherein NR¹¹R¹² together is acyclic amino group substituted with one or more groups selected from theGroup Q (provided that at least one is substituted with a group of theGroup P).

(14) The compound described above in (7), which is

-   [2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic    acid,-   (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)butanedioic    acid,-   2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl    dihydrogen phosphate,-   (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic    acid,-   {2-[({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3    S)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic    acid,-   {2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3R)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic    acid,-   [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-1,1-difluoroethyl]phosphonic    acid,-   {2-[({7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino)ethyl}phosphonic    acid,-   [2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic    acid,-   [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic    acid,-   [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic    acid,-   (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic    acid,-   (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)pentanedioic    acid or-   [2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic    acid, or a pharmaceutically acceptable salt thereof.

(16) The pharmaceutical composition described above in (15), which is aplatelet aggregation inhibitor.

(17) The pharmaceutical composition described above in (15), which is aP2Y12 inhibitor.

(18) Use of the compound described above in any of (7) through (14) as aplatelet aggregation inhibitor.

(19) Use of the compound described above in any of (7) through (14) as aP2Y12 inhibitor.

(20) Use of the compound described above in any of (7) through (14) forproducing a platelet aggregation inhibitor.

(21) Use of the compound described above in any of (7) through (14) forproducing a P2Y12 inhibitor.

Furthermore, the invention relates to a method for therapeuticallytreating circulatory diseases in close relation with thrombosis viaplatelet aggregation, including administering an effective amount of thequinolone derivative represented by the formula (I) or apharmaceutically acceptable salt thereof to a patient.

An active ingredient or compound in accordance with the invention has aquinolone skeleton where the ring atom at position 2 and/or 8 may besubstituted with nitrogen atom and may be condensed together between thebonds at positions 1 and 2, and has a characteristic chemical structurein that the quinolone skeleton has an aminocarbonyl substituent atposition 3 and an amino group substituent at position 7. Additionally,the compound of the invention has a pharmacologically characteristicfeature of platelet aggregation-inhibiting action.

The invention is now described in more detail hereinbelow.

In the present specification, the term “lower” means a linear orbranched carbon chain with one to 6 carbon atoms, unless otherwisestated.

Therefore, the term “lower alkyl” means C₁₋₆ alkyl and specificallyincludes for example methyl, ethyl, propyl, butyl, pentyl or hexyl, orstructural isomers thereof such as isopropyl or tert-butyl. Preferably,the lower alkyl is C₁₋₅ alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl and 3-pentyl.

The term “lower alkenyl” means C₂₋₆ alkyl with one or more double bondsat an appropriate position and specifically includes for exampleethenyl, propenyl, butenyl, pentenyl, hexenyl and butadienyl.Preferably, the lower alkenyl is C₂₋₃ alkenyl, such as ethenyl,1-propenyl, 2-propenyl and 3-propenyl.

The term “lower alkynyl” means C₂₋₆ alkyl with one or more triple bondsat an appropriate position.

The term “lower alkylene” means a divalent group prepared by eliminatingone hydrogen atom at an appropriate position in “lower alkyl” andspecifically includes for example methylene, methylmethylene, ethylene,trimethylene, propylene and butylene. Preferably, the lower alkylene ismethylene, ethylene and trimethylene.

The term “lower alkenylene” means a divalent group prepared byeliminating one hydrogen atom at an appropriate position in “loweralkenyl” and specifically includes for example vinylene, 1-propenylene,2-propenylene, 1-butenylene, 2-butenylene, and 3-butenylene. Preferably,the lower alkenylene is vinylene, l-propenylene and 2-propenylene.

The term “lower alkylidene” means a group with a free atomic valencecomposing a part of the double bond, as prepared after one hydrogenelimination from a carbon atom with a binding ability in the “loweralkyl”.

The term “cycloalkyl” means a monovalent group of non-aromatic C₃₋₈hydrocarbon ring and may form a crosslinked ring or spiro ring or maypartially form an unsaturated bond. Specifically, the cycloalkylincludes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclooctyl, cyclohexenyl, cyclooctandienyl, adamantyl and norbornyl andpreferably includes cyclopentyl or cyclohexyl.

The term “aryl” means a monovalent group of monocyclic to tricyclicaromatic C₆₋₁₄ hydrocarbon ring and specifically includes for examplephenyl and naphthyl. Preferably, the aryl is phenyl.

The term “non-aromatic hetero ring” means a monovalent group of a three-to ten-membered ring, preferably a five- to seven-membered ring withhetero atoms such as nitrogen, oxygen and sulfur, which may partiallyhave an unsaturated bond and may be condensed with an aryl or aromatichetero ring and specifically includes for example pyrrolidinyl,piperidinyl, piperazinyl, azepinyl, morphonyl, thiomorphonyl,pyrazolidinyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrofuryl,dioxanyl, tetrahydrothiopyranyl, and tetrahydrothienyl. Preferably, thenon-aromatic hetero ring is pyrrolidinyl, piperidinyl, piperazinyl,azepinyl, morphonyl, thiomorphonyl, tetrahydropyranyl, dioxanyl andtetrahydrothiopyranyl.

The term “hetero ring” is the generic name of the term “non-aromatichetero ring” including the term “aromatic hetero ring”. The term“aromatic hetero ring” means a monovalent group of an aromatic heteroring containing one to four aromatic hetero atoms which may be the sameor different and is selected from the group of nitrogen, oxygen andsulfur and being satisfactorily condensed with benzene ring andspecifically includes for example pyrrolyl, furyl, thienyl, imidazolyl,pyrazolyl, triazolyl, oxazolyl, thiazolyl, furazanyl, pyridyl, pyranyl,thiopyranyl, pyridazinyl, pyrimidinyl, pyrazyl, indolyl, isoindolyl,indolidinyl, benzofuryl, benzothienyl, benzoimidazolyl, indazolyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazonyl, quinolyl,isoquinolyl, chromenyl, benzothiopyranyl, phthalazinyl, naphthlidinyl,quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl, benzodioxynyl,benzodioxepinyl, and carbazolyl. Nitrogen atom and/or sulfur atomcomposing these rings may be oxidized. Further, these rings may bepartially saturated. Preferably, the monovalent group is pyridyl, furyl,thienyl, indolyl, indazolyl or benzotriazolyl.

The term “halogen” means a monovalent halogen atom group, andspecifically includes for example fluoro, chloro, bromo and iodo andpreferably includes fluoro and chloro.

The term “halogeno-lower alkyl group” means a group where one or moreappropriate hydrogen atoms in the “lower alkyl group” are substitutedwith one or more of the “halogen” described above and specificallyincludes for example trifluoromethyl, and trifluoroethyl. Preferably,the halogeno-lower alkyl group is trifluoromethyl.

The term “cyclic amino” is a monovalent group of a hetero ring with abinding hand to nitrogen atom and may satisfactorily contain oxygen andsulfur as hetero atoms. Specifically, the cyclic amino includespyrrolidino, piperidino, piperazino, homopiperazino, morpholino,thiomorpholino and 3,4-dihydroisoquinolin-2(1H)-yl. Preferably, thecyclic amino is pyrrolidino, piperidino, piperazino, and3,4-dihydrosioquinolin-2(1H)-yl.

In the specification, the substituents acceptable as those for thephrase “which may be substituted” satisfactorily include those forroutine use in the art as substituents for the individual groups.Additionally, one or more substituents which may be the same ordifferent may exist on the individual groups.

The substituents acceptable for the “aryl which may be substituted” inR¹², the “cyclic amino which may be substituted” as represented by R¹¹and R¹² together with adjacent nitrogen; the “cycloalkyl which may besubstituted”, the “aryl which may be substituted”, the “non-aromatichetero ring which may be substituted” and the “aromatic hetero ringwhich may be substituted” in R²; the “cycloalkyl which may besubstituted” and the “non-aromatic hetero ring which may be substituted”in R⁴; and “the cyclic amino which may be substituted” in R⁵ includesubstituents shown below in (a) through (h). Additionally, thesubstituents acceptable for the “lower alkyl which may be substituted”in R¹¹; the “lower alkyl which may be substituted” in R¹²; and the“lower alkyl which may be substituted” and the “lower alkenyl which maybe substituted” in R² include groups shown below in a) through (g).Additionally, R^(z) represents a lower alkyl which may be substitutedwith one or more groups selected from the group consisting of —OH,—O-lower alkyls, aminos which may be substituted with one or two loweralkyls, —CO₂H, —CO₂R^(z), carbamoyl which may be substituted with one ortwo lower alkyls, aryls (the aryls may be substituted with halogens),aromatic hetero rings and halogens.

-   -   (a) Halogens.    -   (b) —OH, —O—R^(z), —O-aryl, —OCO—R^(z), oxo (═O), —OSO₃H,        —OP(O)(O—R^(z))₂, —P(O)(O—R^(z))₂, —OP(O)(OH)(O—R^(z)),        —P(O)(OH)(O—R^(z)), —OP(O)(OH)₂, —P(O)(OH)₂.    -   (c) —SH, —S—R^(z), —S-aryl, —SO—R^(z), —SO-aryl, —SO₂—R^(z),        —SO₃H, —SO₂-aryl, sulfamoyl which may be substituted with one or        two R^(z) groups.    -   (d) Amino which may be substituted with one or two R^(z) groups,        —NHCO—R^(z), —NHCO-aryl, —NHSO₂—R^(z), —NHSO₂-aryl, nitro and        imino (═N—R^(z)).    -   (e) —CHO, —CO—R^(z), —CO₂H, —CO₂—R^(z), carbamoyl which may be        substituted with one or two R^(z) groups or aryls,        —CO-non-aromatic hetero ring (the non-aromatic hetero ring may        be substituted with —CO₂H or —CO₂—R^(z)), and cyano.    -   (f) Aryl or cycloalkyl, provided that the aryl or cycloalkyl may        be substituted individually with one or more groups selected        from the group consisting of —OH, —O-lower alkyls, aminos which        may be substituted with one or two lower alkyls, —CO₂H,        —CO₂R^(z), carbamoyl which may be substituted with one or two        lower alkyls, aryls, aromatic hetero rings, halogens and R^(z).    -   (g) Aromatic hetero ring or non-aromatic hetero ring, provided        that these groups may be substituted individually with one or        more groups selected from the group consisting of —OH, —O-lower        alkyls, oxo (═O), aminos which may be substituted with one or        two lower alkyls, —CO₂H, —CO₂R^(z), carbamoyl which may be        substituted with one or two lower alkyls, aryls, aromatic hetero        rings, halogens and R^(z).    -   (h) Lower alkyl which may be substituted with one or more groups        selected from the substituents described above in (a) through        (g).

Particularly, individual substituents for the “lower alkyl which may besubstituted” and the “aryl which may be substituted” in R¹², orsubstituents for —NR¹¹R¹² integrally composing a cyclic amino group arepreferably one or more substituents selected from the following Group Q.

Group Q: —F, —OH, —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂.

The phrase “amino group which may be substituted with a lower alkylgroup which may be substituted” means an amino group substituted withonly one “lower alkyl group which may be substituted” or two such “loweralkyl groups”. The lower alkyl groups for the di-substitution may be thesame or different.

In the compound, X is preferably CH.

Further, Y is preferably CH or N, more preferably CH.

Additionally, R¹¹ is preferably —H.

R¹² is preferably a lower alkyl group or aryl substituted individuallywith one or more groups selected from the Group Q (provided that atleast one is substituted with a group of the Group P); more preferablymethyl, ethyl, propyl or butyl substituted individually with one or moregroups selected from the Group Q (provided that at least one issubstituted with a group of the Group P)

Herein, the Groups P and Q represent the following groups.

-   -   Group P: —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂; and    -   Group Q: —F, —OH, —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂.

When —NR¹¹R¹² integrally represents a cyclic amino group, it ispreferably a cyclic amino group substituted with one or more groupsselected from the Group Q (provided that at least one is substitutedwith a group of the Group P).

Additionally, R² is preferably a lower alkyl, cycloalkyl or non-aromatichetero ring, which may be individually substituted.

Further, R³ is preferably a halogen, more preferably fluoro.

Still further, R⁴ is preferably a cycloalkyl, more preferablycyclohexyl.

Furthermore, R⁵ is preferably —H, —OH or a halogen, more preferably H,—OH or fluoro, and still more preferably —H or —OH.

And further, R⁶ is preferably —H.

Still further, R⁷ is preferably —H.

The quinolone derivative represented by the formula (I) or (I-a) maysometimes form a salt. Such salt is encompassed within an activeingredient of the invention or the compound of the invention, as long asthe salt is a pharmaceutically acceptable salt. Specifically, the saltincludes salts thereof with inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid; acid addition salts thereof with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, aspartic acid, and glutamic acid; addition saltsthereof with inorganic bases such as sodium, potassium, calcium andmagnesium and organic bases such as methylamine, ethylamine,ethanolamine, lysine and ornithine, and ammonium salts.

An active ingredient or compound of the invention may sometimes includeasymmetric carbon atoms, depending on the substituent type. Therefore,optical isomers based on such carbon atom may exist. These opticalisomers in mixture or in isolation are all encompassed within the scopeof the invention. Additionally, an active ingredient or compound of theinvention may sometimes exist in the forms of tautomeric isomers. Theseisomers in separation or in mixture are also encompassed within thescope of the invention. Additionally, an active ingredient or compoundof the invention after labeling, namely an active ingredient or thecompound with one or more atoms therein being substituted with aradioisotope or a non-radioactive isotope is also encompassed within thescope of the invention.

Furthermore, various hydrates of an active ingredient or compound of theinvention, various solvates thereof and polymorphic substances thereofare also encompassed within the scope of the invention. It is needlessto say that an active ingredient or compound of the invention is notlimited to the compounds described below in the Examples but includesall derivatives represented by the formula (I) or (I-a) and allpharmaceutically acceptable salts thereof.

Furthermore, the compound of the invention encompasses compounds to bemetabolized into an active ingredient or compound of the inventionwithin a living body, namely so-called prodrugs in their entirety. Thegroups forming the prodrugs of the compound of the invention include thegroups described in Prog. Med. 5: 2157-2161 (1985) and the groupsdescribed in “The Development of Pharmaceutical Products (“lyakuhin-noKaihatsu” in Japanese)”, Vol. 7, Molecular Design, pp. 163-198, 1990,Hirokawa Shoten.

(Production Processes)

An active ingredient or compound of the invention can be producedthrough application of various known synthesis processes by utilizingthe characteristic based on the basic skeleton thereof or kinds of thesubstituents. Representative production processes will be enumeratedbelow. Incidentally, in some case, it is effective on the productiontechnology that depending on the kind of a functional group, thefunctional group is replaced by a protective group, i.e., a group thatcan be readily converted into the functional group in a state of thestarting material or intermediates. Thereafter, if desired, theprotective group is removed, thereby enabling to obtain the desiredcompound. Examples of such a functional group include a hydroxyl group,a carboxyl group and an amino group. Examples of the protective groupthereof include the protective groups as described in Greene and Wuts,Protective Groups in Organic Synthesis (third edition), and these may beproperly used depending on the reaction condition.

(In the formula, R¹¹, R¹², R², R³, R⁴, R⁵, R⁶ and X independentlyrepresent the aforementioned groups while Lv represents a leaving group,depending on the reaction; the same is true hereinbelow.)(Step A)

This step is a step of producing a compound (1c) via the condensationand cyclization of the compound (1a) with the compound (1b).

The condensation and cyclization at the step can be carried out in theabsence of any solvent or in the presence of a solvent with a highboiling point (for example diphenyl ether is preferably used) underheating and under reflux under heating.

(Step B)

This step is a step of producing a compound (1e) via the alkylation ofthe compound (1c) with the compound (1d).

The leaving group Lv in the compound (1d) at the step may satisfactorilybe any leaving group for routine use in alkylation. As such, halogenssuch as bromo, iodo and chloro; and sulfonyloxy groups such asmethanesulfonyloxy, p-toluenesulfonyloxy, andtrifluoromethanesulfonyloxy are preferably used. The method described inJ. Med. Chem., 23, 1358-1363, 1980 or a method according to the methodcan be employed.

(Step C)

The step is a step of producing a compound (1g) by substituting theelimination group in the compound (1e) with the amino group in thecompound (1f).

The leaving group Lv in the compound (1e) at the step may be anyelimination for routine use in aromatic nucleophilic substitutionreaction. As such, preferably, use is made of halogens such as fluoro,chloro and bromo; sulfonyloxy groups such as methanesulfonyloxy,p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy; sulfonyl groupssuch as lower alkylsulfonyl and arylsulfonyl. In case that sulfonyl isdefined as the leaving group Lv at the step C, the compound (1a) withsulfonyl as Lv can be used as the starting material. Otherwise, thecompound (1a) with the corresponding sulfanyl as Lv can be used as thestarting material. After an appropriate step for example Step B, then,Lv is modified into sulfonyl via an oxidation reaction using for examplem-chloroperbenzoic acid, for use in the substitution reaction at theStep C.

The substitution reaction at the step can be carried out in the absenceof any solvent or in the presence of solvents inert to the reaction, forexample aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), and dioxane;halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane andchloroform; N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO);esters such as ethyl acetate (EtOAc); acetonitrile; and alcohols such asmethanol (MeOH), ethanol (EtOH) and 2-propanol, at ambient temperatureand under reflux under heating, using an equimolar amount of thecompound (1e) and the compound (1f) or an excess of either one of thecompounds. Depending on the compound, the substitution reaction maysometimes be carried out advantageously in the presence of organic bases(for example triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or basesin the form of metal salts (potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, potassiumtert-butoxide are preferably used).

(Step D)

The step is a step of producing the compound (1h) by subjecting thecompound (1g) to a hydrolysis reaction.

The hydrolysis reaction of the compound (1g) at the step can be carriedout in the presence of acids such as inorganic acids for example mineralacids including for example sulfuric acid, hydrochloric acid andhydrobromic acid and organic acids such as formic acid and acetic acidor in the presence of bases such as lithium hydroxide, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, cesiumcarbonate or ammonia, under cooling and under reflux under heating insolvents inert to the reaction, such as aromatic hydrocarbons, ethers,halogenated hydrocarbons, alcohols, DMF, N,N-dimethylacetamide (DMA),N-methylpyrrolidone, DMSO, pyridine and water. The reaction temperaturecan be selected, appropriately, depending on the compounds and thereaction reagents.

(Step E)

The step is a step of producing the compound (I-b) of the invention viathe amidation of the compound (1h) or a reactive derivative thereof withthe compound (1i).

For the amidation at this step, amidation for routine use by a personskilled in the art can be employed. Preference is given to a processusing condensing agents such as carbonyldiimidazole (CDI),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt(WSC.HCl), dicyclohexylcarbodiimide, diphenylphosphorylazide, anddiethylphosphorylcyanide and a process through a mixed acid anhydride,using isobutyl chloroformate and ethyl chloroformate.

Generally, the step is carried out under cooling, under cooling or atambient temperature, or at ambient temperature and under reflux underheating in solvents inert to the reaction, such as halogenatedhydrocarbons, aromatic hydrocarbons, ethers, DMF and DMSO, although thedetails vary depending on the reactive derivative and the condensingagent to be used.

(Step F)

The step is a step of producing the compound (1j) by subjecting thecompound (1e) to a hydrolysis reaction according to the Step D.

(Step G)

The step is a step of producing the compound (1h) by substituting theelimination group in the compound (1j) with the amino group in thecompound (1f) according to the Step C.

(Step H)

The step is a step of producing the compound (1k) via the amidation ofthe compound (1j) or a reactive derivative thereof with the compound(1i) according to the Step E.

(Step I)

The step is a step of producing the compound (I-b) of the invention bysubstituting the elimination group in the compound (1k) with the aminogroup in the compound (1f) according to the Step C.

(Step J)

The step is a step of producing the compound (1l) via the alkylation ofthe compound (1a). The alkylation at the step can be carried out by aprocess according to the Step B or by reductive alkylation. For thereductive alkylation, reductive alkylation processes for routine use bya person skilled in the art can be employed. For example, the methoddescribed in “Experimental Lecture Series of Chemistry (“Jikken KagakuKoza” in Japanese) (the 4th edition)“, Japan Chemical Association, Vol.20, 1992 (Maruzen) is listed. Generally, the step is preferably carriedout using reducing agents such as sodium borohydride and sodiumtriacetoxyborohydride under cooling, at ambient temperature and underreflux under heating in solvents inert to the reaction, such ashalogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, andacetic acid. Depending on the compound, advantageously, the reaction iscarried out in the presence of acids such as mineral acids including forexample sulfuric acid, hydrochloric acid and hydrobromic acid andorganic acids such as formic acid and acetic acid.

(Step K)

The step is a step of producing the compound (1e) via the condensationand cyclization of the compound (1b) and the compound (1l) according tothe Step A.

The present process through the Step A is a production processemployable in case that the introduction of R² involves difficulty inthe Step B of the first process, depending on the bulkiness oftert-butyl group, adamantyl group and the like. Additionally, theprocess through the Step B is a production process employable in casethat R² and R⁶ together form a ring.

(Step A)

The step is a step of producing the compound (2c) via the condensationof the compound (2a) with orthoformate ester and subsequent addition andelimination with the compound (2b).

The condensation with orthoformate ester at the step can be carried outin a solvent capturing alcohols generated from orthoformate ester suchas acetic anhydride, or via the reaction with a reagent capturingalcohols generated from orthoformate ester in a solvent inert to thereaction, such as halogenated hydrocarbons, ethers, aromatichydrocarbons, DMF, DMSO, esters such as ethyl acetate (EtOAc), andacetonitrile, at ambient temperature and under reflux under heating.

The addition and elimination reaction subsequent to the condensation canbe carried out under cooling, at ambient temperature and under refluxunder heating in solvents inert to the reaction, such as alcohols,halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF and DMSO.An excess of the compound (2c) may be used for the reaction. Dependingon the compound, advantageously, the step may be carried out in thepresence of organic bases (for example triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine are preferably used) or bases in the formof metal salts (for example potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, and potassiumtert-butoxide are preferably used).

(Step B)

The step is a step of producing the compound (2c) via the addition andelimination reaction of the compound (2a) with the compound (2d).

The addition and elimination reaction at the step can be carried out insolvents inert to the reaction, for example halogenated hydrocarbons,ethers, aromatic hydrocarbons, DMF and DMSO, using an equimolar amountof the compound (2a) and the compound (2d) or an excess of either one ofthe compounds, under cooling, at ambient temperature and under refluxunder heating. Depending on the compound, the addition and eliminationreaction may sometimes be carried out advantageously in the presence oforganic bases (for example triethylamine, diisopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine arepreferably used), or bases in the form of metal salts (potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, potassium tert-butoxide are preferably used).

(Step C)

The step is a step of producing the compound (1e) via the intramolecularcyclization of the amino group in the compound (2c).

The addition and elimination reaction of the compound (2c) at this stepcan be carried out under cooling, at ambient temperature and underreflux under heating in solvents inert to the reaction, such ashalogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, and DMSO.Depending on the compound, the addition and elimination reaction maysometimes be carried out advantageously in the presence of organic bases(for example triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or basesin the form of metal salts (potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, potassiumtert-butoxide are preferably used).

The compound (1e) produced at the step is subjected to the processsimilar to the first process, to produce the inventive compound (I-c).

The process is a production process employable in case that R² and R⁶together form a ring.(Step A)

The step is a step of producing the compound (2c) via the condensationof the compound (3a) with the compound (3b).

As the leaving group Lv in the compound (3a) at the step, halogens suchas chloro and bromo, alkoxy, acyloxy and sulfonyloxy such asp-toluenesulfonyl are preferably used. Additionally, the compound (3b′)instead of the compound (3b) at the step can be used, where the positionof the double bond is isomerized.

The condensation reaction at the step can be carried out in solventsinert to the reaction, for example halogenated hydrocarbons, ethers,aromatic hydrocarbons, DMF and DMSO at ambient temperature and underreflux under heating, using an equimolar amount of the compound (3a) andthe compound (3b) or an excess of either one of the compounds. Dependingon the compound, the condensation reaction may sometimes be carried outadvantageously in the presence of organic bases (for exampletriethylamine, diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine are preferably used), or bases in the formof metal salts (potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride, potassium tert-butoxide arepreferably used).

(Step B)

The step is a step of producing the compound (1e) via the cyclizationreaction of the compound (2c).

The intramolecular cyclization reaction at this step can be carried outaccording to the step C of the second process. So as to promote thereaction smoothly at this step, the step is advantageously carried outin the presence of bases in the form of metal salts, such as sodiumhydride.

Depending on the conditions for the step A, the compound (1e) mayinstantly be obtained from the compound (3a) without the isolation ofthe compound (2c).

The compound (1e) produced at the step is subjected to the same processas in the first process, to produce the inventive compound (I-d).

The process is a production process of constructing a fused ring afterthe preliminary introduction of R⁴NH—.(Step A)

The step is a step of producing the compound (4a) by substituting theleaving group in the compound (1a) with the amino group in the compound(1f) according to the step C of the first process.

Additionally, the step may be carried out via a substitution reactionusing a palladium catalyst (in this case, halogens such as bromo andiodo and trifluoromethanesulfonyloxy are preferably used as the Lv inthe compound (1a)), according to the method described in TetrahedronLett., 38, 6359-6362, 1997 or a process according to the method.

(Step B)

The step is a step of producing the compound (4b) via the condensationand cyclization reaction of the compound (4a) with the compound (1b)according to the step A of the first process.

(Step C)

The step is a step of producing the compound (4c) via the alkylationreaction of the compound (4b) and the compound (1d) according to thestep B of the first process.

(Step D)

The step is a step of producing the compound (1h) by subjecting thecompound (4c) to a hydrolysis reaction according to the step D of thefirst process.

(Step E)

The step is a step of producing the inventive compound (I-e) via theamidation of the compound (1h) or a reactive derivative thereof with thecompound (1i) according to the step E of the first process.

The process is a process of producing a compound of the formula (I) or(I-a) where Y is N.(Step A)

The step is a step of producing the compound (5b) by preparing thecompound (5a) into a diazo compound and subsequently adding ethylcyanoacetate to the resulting diazo compound.

The diazo preparation as the first stage of the step can be carried outin the presence of acids such as hydrochloric acid, sulfuric acid andacetic acid, in solvents inert to the reaction, such as water andalcohol, using an equimolar amount of a reagent for preparing diazocompounds such as sodium nitrite and amyl nitrite and the compound (5a)or an excess of either one of the compounds, under cooling. The additionreaction at the second stage can be carried out in the presence of abase, using an equimolar amount of the diazo compound produced at thefirst stage and ethyl cyanoacetate or an excess of either one of themunder cooling, at ambient temperature and under reflux under heating. Asthe base, organic bases (for example triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine are preferably used), or bases in the formof metal salts (potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride, potassium tert-butoxide arepreferably used) can be used.

(Step B)

The step is a step of producing the compound (5c) via the alkylationreaction of the compound (5b) and the compound (1d) according to thestep B of the first process.

(Step C)

The step is a step of producing the compound (5d) by subjecting thecompound (5c) to a hydrolysis reaction according to the step D of thefirst process.

(Step D)

The step is a step of producing the compound (5e) by subjecting thecompound (5d) to acid halogenation and cyclization.

The acid halogenation as the first stage of the step can be carried outin the absence of any solvent or in solvents inert to the reaction, suchas aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters suchas ethyl acetate, and acetonitrile, using an equimolar amount or anexcess of a halogenation agent such as thionyl chloride and oxalylchloride and the compound (5d) under cooling, at ambient temperature andunder reflux under cooling. Depending on the compound, the reaction maysometimes be carried out advantageously by adding a catalytic amount ofDMF and the like. The cyclization reaction as the second stage can becarried out by using the acid halide obtained at the first stage and anequimolar amount or an excess of an Lewis acid in the presence of Lewisacids such as aluminum chloride, in the absence of any solvent or insolvents inert to the reaction such as aromatic hydrocarbons,halogenated hydrocarbons, and esters such as ethyl acetate undercooling, at ambient temperature and under reflux under heating.

(Step E)

The step is a step of producing the compound (5f) by substituting theleaving group in the compound (5e) with the amino group in the compound(1f) according to the step C of the first process.

(Step F)

The step is a step of producing the compound (5d) by subjecting thecompound (5f) to a hydrolysis reaction according to the step D of thefirst process.

(Step G)

The step is a step of producing the inventive compound (I-f) via theamidation of the compound (5g) or a reactive derivative thereof and thecompound (1i) according to the step E of the first process.

The process is a process of producing the compound of the formula (I) or(I-a) where Y is N.(Step A)

The step is a step of producing the compound (6a) via the preparation ofthe compound (2a) into a diazo compound.

The diazo-preparing reaction at this step can be done using an equimolaramount of a diazo-preparing reagent such as sodium azide andp-toluenesulfonyl azide and the compound (2a) or an excess of either oneof the compounds in solvents inert to the reaction, for examplehydrocarbons such as pentene and hexane, aromatic hydrocarbons, ethers,halogenated hydrocarbons, alcohols, acetonitrile and water, at ambienttemperature and under reflux under heating. Depending on the compound,the reaction may sometimes be carried out advantageously in the presenceof organic bases (for example triethylamine, diisopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine arepreferably used), or bases in the form of metal salts (potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, potassium tert-butoxide are preferably used).

(Step B)

The step is a step of producing the compound (6b) via the reductiveintramolecular cyclization reaction of the compound (6a).

At this step, trialkylphosphine or triarylphosphine can be used as thereducing agent. As the leaving group Lv in the compound (6a), forexample, halogens such as fluoro, chloro and bromo, sulfonyloxy such asp-toluenesulfonyl and nitro are used. The use of fluoro is particularlypreferable. For this step, the method described in Chem. Pharm. Bull.,36, 1321-1327, 1988 or a method according to the method can be employed.

(Step C)

The step is a step of producing the compound (6c) via the alkylationreaction of the compound (6b) and the compound (1d) according to thestep B of the first process.

(Step D)

The step is a step of producing the compound (6d) by substituting theleaving group in the compound (6c) with the amino group in the compound(1f) according to the step C of the first process.

(Step E)

The step is a step of producing the compound (6e) by subjecting thecompound (6d) to a hydrolysis reaction according to the step D of thefirst process.

(Step F)

The step is a step of producing the inventive compound (I-g) via theamidation of the compound (6e) or a reactive derivative thereof and thecompound (1i) according to the step E of the first process.

(In the formula, R⁸ represents a lower alkenyl or a lower alkynyl withan unsaturated bond at position β, such as allyl and propargyl, whichmay be substituted; R⁹ and R¹⁰ represents H or a lower alkyl group;otherwise, R⁹ and R¹⁰ together may represent a lower alkylidene; and mand n represent 0 to 3.)

The process is a process of producing the compound of the formula (I) or(I-a), where R² and R⁶ together form a ring.

(Step A)

The step is a step of producing the compound (7b) via the alkylationreaction of the compound (1c′) and the compound (7a).

The alkylation reaction at this step can be done, using an equimolaramount of the compound (1c′) and the compound (7a) or an excess ofeither one of the compounds in the absence of any solvent or in solventsinert to the reaction, for example aromatic hydrocarbons, ethers,halogenated hydrocarbons, DMF, DMSO, esters such as ethyl acetate, andacetonitrile or in solvents such as alcohol, at ambient temperature andunder reflux under heating. Depending on the compound, the substitutionreaction may sometimes be carried out advantageously in the presence oforganic bases (for example triethylamine, diisopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine arepreferably used), or bases in the form of metal salts (potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, potassium tert-butoxide are preferably used).

(Step B)

The step is a step of producing the compound (7c) via the intramolecularrearrangement reaction of the compound (7b).

The cyclization reaction at this step can be done in the absence of anysolvent or in the presence of a solvent with a high boiling point (forexample 1,2-dichlorobenzene is preferably used) under heating and underreflux under heating.

(Step C)

The step is a step of producing the inventive compound (1e′) via theintramolecular cyclization reaction of the compound (7c) in case that R⁸has an leaving group such as halogens (chloro and bromo are preferablyused) and sulfonyloxy (methanesulfonyloxy and p-toluenesulfonyloxy arepreferably used) or a triple bond.

The intramolecular cyclization reaction of the compound (7c) at thisstep can be done in the absence of any solvent or in solvents inert tothe reaction, such as halogenated hydrocarbons, ethers, aromatichydrocarbons, DMF and DMSO, under cooling, at ambient temperature andunder reflux under heating. Depending on the compound, the reaction maysometimes be carried out advantageously in the presence of organic bases(for example triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or basesin the form of metal salts (potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, potassiumtert-butoxide are preferably used).

Depending on the conditions for the step B, further, the compound (1e′)may sometimes be obtained instantly from the compound (7b) withoutisolation of the compound (7c).

The compound (1e′) produced at the step is subjected to the same processas the first process, to produce the inventive compound (I-h).

Additionally, some compounds represented by the formula (I) or (I-a) mayalso be produced from the inventive compounds thus obtained by anappropriate combination of known steps for routine use by a personskilled in the art, such as alkylation, acylation, substitution,oxidation, reduction and hydrolysis.

The inventive compounds thus produced are isolated and purified as theyare free or are isolated and purified as salts prepared by generalmethods. The isolation and purification are done by general chemicalprocedures such as extraction, concentration, distillation,crystallization, filtration, recrystallization, and variouschromatographic means.

Various isomers can be isolated by general methods, utilizing thedifference in physico-chemical properties between the isomers. Forexample, a racemic mixture can be prepared into an optically pure isomerby a general racemic resolution method including for example preparing adiastereomer salt with a general optically active acid such as tartaricacid and subsequent optical resolution. Additionally, a diastereomermixture can be separated for example by fractional crystallization orvarious chromatographic means. Still further, optically active compoundscan be produced by using appropriate optically active startingmaterials.

INDUSTRIAL APPLICABILITY

An active ingredient or compound of the invention has an excellentplatelet aggregation-inhibiting action and an excellent P2Y12-inhibitingaction. Therefore, an active ingredient or compound of the invention isuseful as a pharmaceutical agent, particularly a platelet aggregationinhibitor and a P2Y12 inhibitor. Accordingly, an active ingredient orcompound of the invention is useful as a prophylactic and/or therapeuticagent of circulatory diseases in close relation with thrombosis viaplatelet aggregation, including ischemic disorders for example unstableangina, acute myocardial infarction and secondary onsets thereof,re-occlusion and re-stenosis post-liver artery bypass surgery, post-PTCAor post-stenting, thrombolytic promotion of liver artery and prophylaxisof re-occlusion; cerebral vascular disorders such as transient cerebralischemia attack (TIA), cerebral stenosis, and subarachnoid hemorrhage(vascular constriction): and peripheral artery diseases such as chronicartery occlusion; as well as an aiding agent during heart surgery orvascular surgery.

The excellent platelet aggregation-inhibiting action of the inventivecompound was verified by the following test methods.

(1) Test for Assaying Human Platelet Aggregation-Inhibiting Activity

Blood was withdrawn from healthy human volunteers (adult males), in thepresence of a 1/10th volume of sodium citrate, and centrifuged-to obtainsupernatant platelet-enriched plasma (PRP). The platelet count in PRPwas determined with an automatic blood cell counter (MEK-6258;manufactured by NIHON KOHDEN CORPORATION). Then, the platelet count inPRP was adjusted to 3×10⁸/ml with platelet-poor plasma. ADP as aplatelet aggregation-inducing agent was a product of MCMEDICAL, Inc.Platelet aggregation was measured using an aggregometer (MCM Hematracer212; MCMEDICAL, Inc.). Specifically, 80 μl of PRP and 10 μl of asolution of an active ingredient or compound of the invention or asolvent (10% DMSO) were incubated together at 37° C. for one minute, towhich 10 μl of ADP (50 μM) was added to induce platelet aggregation.Then, the change of the transmitting light was recorded over 5 minutes.Using the area-under-the curve of platelet aggregation as an indicator,the inhibition ratio was calculated. The results from an activeingredient or compound of the invention at 10 μM (as finalconcentration) are shown in Table 1. TABLE 1 Human plateletaggregation-inhibiting action Test compound % inhibition Example 18 92Example 419 88 Example 429 88 Example 522 86 Example 557 81 Example 58392 Example 603 81 Example 619 91(2) Substitution Test of the Binding Between Human P2Y12 and2-methylthio-ADP (2-MeS-ADP)

After C6-15 cells were inoculated on a DMEM culture medium to 1×10⁶cells in a 10-cm petri dish for culturing for one day, where 8 μg of aplasmid pEF-BOS-dhfr-human P2Y12 and 0.8 μg of pEF-BOS-neo (Nucleic AcidRes., 18,5322, 1990) were genetically introduced with a transfectionreagent (LipofectAMINE 2000; manufactured by GIBCO BRL).

24 hours after the gene introduction procedure described above, thecells with the gene introduced therein were recovered and suspended in aDMEM culture medium containing 0.6 mg/ml G418 (manufactured by GIBCOBRL), to prepare serial dilutions, which were inoculated on a 10-cmpetri dish. Colonies appearing 2 weeks later were individually obtainedand defined as C6-15 cell expressing the protein P2Y12, for use in thefollowing experiment (WO 02/36631, Mol. Pharmacol., 60, 432,2001).

The C6-15 cell expressing the protein P2Y12 was cultured and recovered.After the cell was rinsed with PBS, the cell was suspended in 20 mMTris-HCl, pH 7.4 containing 5 mmol/l EDTA and a protease inhibitorcocktail set Complete™ (manufactured by Boehringer Mannheim GmbH) andthen homogenized with Polytron. After ultra-centrifugation, theresulting precipitate was suspended in 50 mM Tris-HCl, pH 7.4 containing1 mM EDTA, 100 mM NaCl and Complete™. The resulting suspension wasdefined as a membrane fraction.

1.5 μl of an active ingredient or compound of the invention and 50 μl of0.75 nM [³H]-2-MeS-ADP (80 Ci/mmol; manufactured by Amersham PharmaciaBiotech) were added to 100 μl of the P2Y12 protein-expressing C6-15 cellmembrane fraction (100 μg/ml) thus prepared, for incubation in 50 mMTris-HCl, pH 7.4 containing 100 mM NaCl and 50 mM MgCl₂, at ambienttemperature for one hour. Subsequently, the incubation mixture wasrecovered onto a glass filter with a cell harvester. Adding amicroscintillator onto the glass filter, the radioactivity was assayedwith a liquid scintillation counter. At the test, additionally, theradioactivity levels of such cell cultures with no addition of thecompound and with addition of 1.5 μl of 100 μM 2-MeS-ADP were assayed astotal binding and non-specific binding, respectively. Defining the totalbinding and the non-specific binding at inhibition ratios of 0% and100%, respectively, the inhibition ratio (%) of an active ingredient orcompound in accordance with the invention was calculated. The resultsfrom an active ingredient or the compound of the invention at 30 nM(final concentration) are shown in Table 2. TABLE 2 Inhibition activityof the binding between P2Y12 and 2-MeS-ADP Test compounds % inhibitionExample 18 96 Example 22 75 Example 28 63 Example 178 30 Example 259 52Example 265 40 Example 279 31 Example 290 74 Example 336 46 Example 40680 Example 425 93 Example 429 98 Example 463 62 Example 501 95 Example522 80 Example 532 36 Example 583 80 Example 619 73

A pharmaceutical composition comprising an active ingredient of theinvention is prepared into tablets, powders, fine granules, granules,capsules, pills, liquids, injections, suppositories, ointments and paps,using carriers and excipients and other additives for general use, fororal or parenteral administration.

The clinical dose of an active ingredient of the invention isappropriately determined, taking account of for example the symptoms,body weight, age and sex of a patient to be administered. Generally, thedaily oral dose is generally about 0.0001 to 50 mg/kg, preferably about0.001 to 10 mg/kg, more preferably about 0.01 to 1 mg/kg, in one portionor in divided portions of 2 to 4. For intravenous administration,appropriately, the daily dose is appropriately about 0.0001 to 1 mg/kg,preferably about 0.0001 to 0.1 mg/kg per body weight, in one portion perday or in divided plural portions per day. The dose varies depending onthe variable conditions. Therefore, a sufficient effect may sometimes beobtained at an amount smaller than the ranges of the doses.

As a solid composition for oral administration in accordance with theinvention, for example, tablets, powders and granules are used. In suchsolid composition, one or more active substances are mixed with at leastone inactive diluent type, including for example lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, and magnesium metasilicate aluminate. Thecomposition may satisfactorily contain additives other than the inactivediluents, for example lubricants such as magnesium stearate,disintegrators such as fibrin calcium glycolate, stabilizers andauxiliary agents for dissolution. If necessary, the tablets and pillsmay be coated with sugar coatings of sucrose, gelatin, hydroxypropylcellulose, and hydroxypropylmethyl cellulose phthalate or with filmsdissolvable in stomach or intestine.

The liquid composition for oral administration contains for examplepharmaceutically acceptable emulsifiers, fluids, suspending agents,syrups and elixirs and also contain inactive diluents for general use,including for example distilled water, and ethanol (EtOH). Thecomposition may satisfactorily contain auxiliary agents such asemollients and suspending agents, sweeteners, flavors, aromatic agentsand preservatives other than the inactive diluents.

The injections for parenteral administration contain sterile, aqueous ornon-aqueous fluids, suspending agents and emulsifiers. The aqueousfluids and the suspending agents include for example distilled water forinjections and physiological saline. The non-aqueous fluids andsuspending agents include for example propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, alcohols such as EtOH,polysorbate 80. Such composition further may contain preservatives,emollients, emulsifiers, dispersants, stabilizers and auxiliary agentsfor dissolution. These are sterilized by for example filtration throughbacteria-deposit filters, blending of sterilizing agents or irradiation.These may also be used in a form of a sterile solid composition, whichis preliminarily dissolved in sterile water or sterile solvents forinjections.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention is now specifically described in the following Examplesbut is never limited to these Examples. Herein, the starting materialcompounds for use in the Examples include novel substances. Theprocesses from such starting material compounds are described inReference Examples.

The symbols in the Tables represent the following meanings (the same istrue hereinbelow).

-   -   Rf: Number of Reference Example    -   Ex: Number of Example

(In case that only the number of Example is described in the column Ex,the compound is in the free form; in case that a diagonal line (/) andHCl are added after the number of Example, the compound is in the formof hydrochloride salt.)

Data: Physical data [Sal: Salt (no description of Sal indicates freeform; in case that for example HCl is added, the compound is in the formof hydrochloride salt.)]

R, R¹, R², R³, R⁴, A: substituent groups in general formulas (Me:methyl; Et: ethyl; nPr: n-propyl; iPr: isopropyl; iBu: isobutyl; sBu:sec-butyl; tBu: tert-butyl; nPen: n-pentyl; cPr: cyclopropyl; cBu:cyclobutyl; cPen: cyclopentyl; cHex: cyclohexyl; cHep: cycloheptyl;cOct: cyclooctyl; Ph: phenyl; Py: pyridyl; fur: furyl; the: thienyl; Bn:benzyl; btria: benzotriazolyl; bimid: benzoimidazolyl; pyrr:pyrrolidinyl; pipe: piperidinyl; pipa: piperazinyl; mor: morpholinyl;THF: tetrahydrofuranyl; THP: tetrahydropyranyl; THSP:tetrahydrothiopyranyl; 2-thiq: 3,4-dihydroisoquinolin-2(1H)-yl; Boc:tert-butyloxycarbonyl; Ac: acetyl; Bz: benzoyl; tri: tri; di: di. Thenumber before a substituent group expresses the position substituted.Accordingly, for example, 4-EtO₂C-1-pipe represents4-ethoxycarbonylpiperidin-1-yl and 2-the-(CH₂)₂—NH— represents2-(thiophen-2-yl)ethylamino.) Syn: production process (a numericalfigure indicates the use of a corresponding starting material forproduction, like a compound of Example with the numerical figure; whentwo or more numbers are written, the production is done, using numberedproduction processes sequentially from the preceding numbers.)

REFERENCE EXAMPLE 1

3-Bromo-4-fluorobenzoic acid was dissolved in toluene, to whichtert-butanol, triethylamine and diphenylphosphorylazide weresequentially added to stir at 100° C. for 20 hours, to obtain tert-butyl(3-bromo-4-fluorophenyl)carbamate.

FAB-MS(Neg): 288, 290 (M⁺−1)

REFERENCE EXAMPLE 2

The compound of Reference Example 1 was dissolved in toluene, to whichaniline, cesium carbonate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,and tris(dibenzylidene acetone)dipalladium were sequentially added forstirring at 110° C. for 2 days, to obtain tert-butyl(3-anilino-4-fluorophenyl)carbamate. The resulting compound wasdissolved in EtOAc, to which 4M HCl-EtOAc solution was added forstirring at ambient temperature for one day, to obtain4-fluoro-N³-phenylbenzene-1,3-diamine.

FAB-MS(Pos): 203 (M⁺+1)

REFERENCE EXAMPLE 3

Diethyl ethoxymethylenemalonate was added to 3,4-difluoroaniline atambient temperature and the mixture was stirred at 130° C. for 17 hours.After diphenyl ether was additionally added to the reaction mixture,stirring was done at 260° C. for one hour. A solid obtained by leavingthe reaction mixture to stand for cooling to ambient temperature wasfiltered, to obtain ethyl6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

In the same manner as in the process of Reference Example 3, ReferenceExamples 4 through 10 in Table 3 were produced using the respectivecorresponding starting materials. TABLE 3

Rf R¹ R² R³ R⁴ Data 3 H F F H FAB-MS(Pos); 254(M⁺ + 1) 4 H Br F HFAB-MS(Pos); 314, 316(M⁺ + 1) 5 H F Ph- H FAB-MS(Pos); 327(M⁺ + 1) NH— 6H H F H FAB-MS(Pos); 236(M⁺ + 1) 7 H F F F FAB-MS(Pos); 272(M⁺ + 1) 8 HCl F H FAB-MS(Pos); 270(M⁺ + 1) 9 H Me F H FAB-MS(Pos); 250(M⁺ + 1) 10 FF F H FAB-MS(Pos); 272(M⁺ + 1)

REFERENCE EXAMPLE 11

Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate produced accordingto Organic Preparations and Procedures International, 29, 231-234, 1997was dissolved in acetic anhydride, to which ethyl orthoformate was addedat ambient temperature, for stirring at 150° C. for one hour. Theresulting mixture was concentrated under reduced pressure. The resultingresidue was dissolved in EtOH, to which cyclopentylamine was added underice cooling, for stirring at ambient temperature for one hour. Theresulting mixture was concentrated under reduced pressure. The resultingresidue was dissolved in 1,4-dioxane, to which 60% sodium hydride wasadded at ambient temperature, for stirring at 80° C. for 4 hours andsubsequent concentration under reduced pressure. Then, aqueoushydrochloric acid solution was added to the resulting concentrate forchloroform extraction. The resulting organic layer was dried overanhydrous sodium sulfate and concentrated. The obtained residue wasdissolved in acetic acid, to which aqueous 6 M HCl was added at ambienttemperature for stirring at 120° C. for 5.5 hours, to obtain1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

In the same manner as in the process of Reference Example 11, ReferenceExamples 12 through 28 as shown in Table 4 were produced using therespective corresponding starting materials. TABLE 4

Rf R Data 11 cPen FAB-MS(Pos); 294(M⁺ + 1) 12 iPr FAB-MS(Pos);268(M⁺ + 1) 13 Ph FAB-MS(Pos); 3O2(M⁺ + 1) 14 cHex FAB-MS(Pos);308(M⁺ + 1) 15 cBu FAB-MS(Pos); 280(M⁺ + 1) 16 sBu FAB-MS(Pos);282(M⁺ + 1) 17

FAB-MS(Pos); 320(M⁺ + 1) 18 (Et)₂CH— FAB-MS(Pos); 296(M⁺ + 1) 19iPr-CH(Me)- FAB-MS(Pos); 296(M⁺ + 1) 20 nPr-CH(Me)- FAB-MS(Pos);296(M⁺ + 1) 21 CF₃CH₂— FAB-MS(Pos); 308(M⁺ + 1) 22 t-Bu-CH(Me)-FAB-MS(Pos); 310(M⁺ + 1) 23 nPr-CH(Et)- FAB-MS(Pos); 310(M⁺ + 1) 24 iBuFAB-MS(Pos); 282(M⁺ + 1) 25 cPr FAB-MS(Pos); 266(M⁺ + 1) 26 iBu-CH(Me)-FAB-MS(Pos); 310(M⁺ + 1) 27 (nPr)₂CH— FAB-MS(Pos); 324(M⁺ + 1) 284,4-diMe-cHex FAB-MS(Pos); 336(M⁺ + 1)

REFERENCE EXAMPLE 29

The compound of Reference Example 5 was suspended in DMF, to whichpotassium carbonate and ethyl iodide were sequentially added under icecooling, for stirring at ambient temperature for 4 days, to obtain ethyl7-anilino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate. Thecompound was suspended in aqueous 1M NaOH, for stirring at 100° C. forone hour, to obtain7-anilino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

FAB-MS(Pos): 327 (M⁺+1)

REFERENCE EXAMPLE 30

The compound of Reference Example 3 was suspended in DMF, to whichpotassium carbonate and ethyl iodide were sequentially added under icecooling, for stirring at ambient temperature for 24 hours and subsequentchloroform extraction. The resulting extract was concentrated underreduced pressure. The resulting residue was suspended in acetic acid, towhich aqueous 6M HCl was added at ambient temperature for stirring at120° C. for 4 hours, to obtain6,7-difluoro-1-ethyl4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

In the same manner as in the process of Reference Example 30, ReferenceExamples 31 through 39 as shown in Table 5 were produced using therespective corresponding starting materials. TABLE 5

Rf R¹ R² R Data 30 F H Et FAB-MS(Pos); 254(M⁺ + 1) 31 F H MeFAB-MS(Pos); 240(M⁺ + 1) 32 F H Rn FAB-MS(Pos); 316(M⁺ + 1) 33 F H4-MeO-Bn FAB-MS(Pos); 346(M⁺ + 1) 34 F H allyl FAB-MS(Pos); 266(M⁺ + 1)35 H H Et FAB-MS(Pos); 236(M⁺ + 1) 36 Br H Et FAB-MS(Pos); 314,316(M⁺ + 1) 37 F F Et FAB-MS(Pos); 272(M⁺ + 1) 38 Cl H Et FAB-MS(Pos);270(M⁺ + 1) 39 Me H Et FAB-MS(Pos); 250(M⁺ + 1)

REFERENCE EXAMPLE 40

The compound of Reference Example 30 was suspended in DMSO, to whichcyclohexylamine was added at ambient temperature, for stirring at 80° C.for 2 hours and subsequent recrystallization in aqueous 80% acetic acidsolution, to obtain7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

NMR(DMSO-d₆) δ; 1.10-1.25(m,1H), 1.27-1.50(m,7H), 1.60-1.70(m,1H),1.72-1.82(m,2H), 1.90-2.00(m,2H), 3.55-3.67(m,1H), 4.53(q,J=7.4 Hz,2H),6.65(dd,J=2.2,8.1 Hz,1H), 6.79(d,J=7.4 Hz,1H), 7.79(d,J=11.3 Hz,1H),8.83(s,1H), 15.78(s,1H)

In the same manner as in the process of Reference Example 40, ReferenceExamples 41 through 87 as shown in Tables 6 and 7 were produced usingthe respective corresponding starting materials. TABLE 6

Rf R¹ R² Data 40 Et cHex FAB-MS(Pos); 333(M⁺ + 1) 41 Et iPr FAB-MS(Pos);293(M⁺ + 1) 42 Et tBu FAB-MS(Pos); 307(M⁺ + 1) 43 Et 4-THP FAB-MS(Pos);335(M⁺ + 1) 44 Et cPen FAB-MS(Pos); 319(M⁺ + 1) 45 Et 1-Boc-4-pipeFAB-MS(Pos); 434(M⁺ + 1) 46 Et Ph FAB-MS(Pos); 327(M⁺ + 1) 47 Et cHepFAB-MS(Pos); 347(M⁺ + 1) 48 Et cOct FAB-MS(Pos); 361(M⁺ + 1) 49 Et1-Me-cHex FAB-MS(Pos); 347(M⁺ + 1) 50 Et 4-THSP FAB-MS(Pos); 351(M⁺ + 1)51 Et 4-Me-cHex FAB-MS(Pos); 347(M⁺ + 1) 52 Et 4,4-diF-cHex FAB-MS(Pos);369(M⁺ + 1) 53 cPen 4-THSP FAB-MS(Pos); 391(M⁺ + 1) 54 cPen 4,4-diF-cHexFAB-MS(Pos); 409(M⁺ + 1) 55 cPen 3-THP FAB-MS(Pos); 375(M⁺ + 1)

TABLE 7

Rf R¹ R² R³ R Data 56 H F H Me FAB-MS(Pos); 319(M⁺ + 1) 57 H F H iPrFAB-MS(Pos); 347(M⁺ + 1) 58 H F H Bn FAB-MS(Pos); 395(M⁺ + 1) 59 H F HcPen FAB-MS(Pos); 373(M⁺ + 1) 60 H F H 4-MeO-Bn FAB-MS(Pos); 425(M⁺ + 1)61 H F H Ph FAB-MS(Pos); 381(M⁺ + 1) 62 H F H cHex FAB-MS(Pos);387(M⁺ + 1) 63 H F H allyl FAB-MS(Pos); 345(M⁺ + 1) 64 H H H EtFAB-MS(Pos); 315(M⁺ + 1) 65 H Br H Et FAB-MS(Pos); 393, 395(M⁺ + 1) 66 HF F Et FAB-MS(Pos); 351(M⁺ + 1) 67 H Cl H Et FAB-MS(Pos); 349(M⁺ + 1) 68H Me H Et FAB-MS(Pos); 329(M⁺ + 1) 69 H F H cBu FAB-MS(Pos); 359(M⁺ + 1)70 H F H sBu FAB-MS(Pos); 361(M⁺ + 1) 71 H F H

FAB-MS(Pos); 399(M⁺ + 1) 72 H F H (Et)₂CH— FAB-MS(Pos); 375(M⁺ + 1) 73 HF H iPr-CH(Me)- FAB-MS(Pos); 375(M⁺ + 1) 74 H F H nPr-CH(Me)-FAB-MS(Pos); 375(M⁺ + 1) 75 H F H CF₃CH₂— FAB-MS(Pos); 387(M⁺ + 1) 76 HF H t-Bu-CH(Me)- FAB-MS(Pos); 389(M⁺ + 1) 77 H F H nPr-CH(Et)-FAB-MS(Pos); 389(M⁺ + 1) 78 H F H iBu FAB-MS(Pos); 361(M⁺ + 1) 79 H F HcPr FAB-MS(Pos); 345(M⁺ + 1) 80 H F H iBu-CH(Et)- FAB-MS(Pos);389(M⁺ + 1) 81 H F H (nPr)₂CH— FAB-MS(Pos); 403(M⁺ + 1) 82 H F H4,4-diMe-cHex FAB-MS(Pos); 415(M⁺ + 1) 83 H F H (FCH₂)₂CH— FAB-MS(Pos);383(M⁺ + 1) 84 H F H H₂C═C(CH₂F)— FAB-MS(Pos); 363(M⁺ + 1) 85 NHMe F HEt ESI-MS(Pos); 362(M⁺ + 1) 86 NH(cHex) F H Et FAB-MS(Pos); 430(M⁺ + 1)87 NH2 F H Et FAB-MS(Pos); 348(M⁺ + 1)

REFERENCE EXAMPLE 88

The compound of Reference Example 10 was dissolved in DMF, to whichpotassium carbonate and ethyl iodide were sequentially added under icecooling, for stirring at ambient temperature for 2 days, to obtain ethyl1-ethyl-5,6,7-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

In the same manner as in the process of Reference Example 88, ReferenceExamples 89 through 91 as shown in Table 8 were produced using therespective corresponding starting materials. TABLE 8 Rf R¹ R Data 88 FEt FAB-MS(Pos); 300(M⁺ + 1) 89 H (1,3-dioxolan-2-yl)-CH₂— FAB-MS(Pos);340(M⁺ + 1) 90 H tBuO₂CCH₂— FAB-MS(Pos); 368(M⁺ + 1) 91 H tBuO₂CCH(Me)-FAB-MS(Pos); 382(M⁺ + 1)

REFERENCE EXAMPLES 92 AND 93

The compound of Reference Example 88 was dissolved in DMSO, to whichcyclohexylamine was added for stirring at 80° C. for one hour, to obtainethyl7-(cyclohexylamino)-1-ethyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(Reference Example 92) and ethyl5-(cyclohexylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(Reference Example 93).

REFERENCE EXAMPLE 93 FAB-MS(Pos): 379 (M⁺+1)

In the same manner as in the process of Reference Example 92, ReferenceExamples 94 through 103 and Reference Examples 104 through 106 as shownin Tables 9 and 10 were produced using the respective correspondingstarting materials. TABLE 9

Rf R¹ R A Data 92 F Et CH FAB-MS(Pos); 379(M⁺ + 1) 94 H(1,3-dioxolan-2-yl)-CH₂— CH FAB-MS(Pos); 419(M⁺ + 1) 95 H tBuO₂CCH₂— CHFAB-MS(Pos); 447(M⁺ + 1) 96 OMe Et CH ESI-MS(Pos); 392(M⁺ + 1) 97 HtBuO₂CCH(Me)- CH ESI-MS(Pos); 461(M⁺ + 1) 98 H cPen N FAB-MS(Pos);402(M⁺ + 1) 99 F (Et)₂CH— CH FAB-MS(Pos); 421(M⁺ + 1) 100 AcN(Me)-(Et)₂CH— CH ESI-MS(Pos); 474(M⁺ + 1)

TABLE 10

Rf —R¹—R²— Data 101 —(CH₂)₃— ESI-MS(Pos); 373(M⁺ + 1) 102—C(═CH₂)—(CH₂)₂— ESI-MS(Pos); 385(M⁺ + 1) 103 —CH₂—C(═CH₂)—(CH₂)₂—ESI-MS(Pos); 399(M⁺ + 1)

REFERENCE EXAMPLE 104

Ethyl7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS(Pos): 415 (M⁺+1)

REFERENCE EXAMPLE 105

Ethyl9-(cyclohexylamino)-8-fluoro-6-oxo-6H-pyrido[1,2-a]quinoline-5-carboxylate

FAB-MS(Pos): 383 (M⁺+1)

REFERENCE EXAMPLE 106

Ethyl[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydro-1,8-naphthylidin-3-yl]carboxylate

FAB-MS(Pos): 376 (M⁺+1)

REFERENCE EXAMPLE 107

Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloridewere added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate indioxane, for stirring at ambient temperature for 30 minutes and at 65°C. for one hour, to obtain ethyl3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate.

FAB-MS(Pos): 356 (M⁺+1)

REFERENCE EXAMPLE 108

60% sodium hydride was added to a solution of the compound of ReferenceExample 107 in dioxane, for stirring at 70° C. for 2 hours, to obtainethyl1-cyclopentyl-6,7-difluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 336 (M⁺+1)

REFERENCE EXAMPLE 109

Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate was dissolved inacetic anhydride, to which ethyl orthoformate was added at ambienttemperature, for stirring at 140° C. for 12 hours and subsequentconcentration under reduced pressure. The resulting residue wasdissolved in EtOH, to which triethylamine and EtOH solution oftetrahydrofuran-3-amine hydrochloride was added under ice cooling, forstirring under ice cooling for 30 minutes and at ambient temperature forone hour. Water was then added for ethyl acetate extraction. Theresulting extract was dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. 60% sodium hydride wasadded to a suspension of the resulting residue in 1,4-dioxane, forstirring at 80° C. for 1.5 hours, to obtain ethyl6,7-difluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-carboxylate.The product was suspended in DMSO, to which cyclohexylamine was added,for stirring at 100° C. for 22 hours, to obtain ethyl7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-carboxylate.

In the same manner as in the process of Reference Example 109, ReferenceExamples 110 through 125 as shown in Table 11 were produced using therespective corresponding starting materials (In Reference Examples 123and 124, the hydroxyl group in the corresponding starting materials wasprotected with tert-butyldimethylsilyl group). TABLE 11

Rf R Data 109 3-THF FAB-MS(Pos); 403(M⁺ + 1) 1102,2-diMe-1,3-dioxan-5-yl FAB-MS(Pos); 447(M⁺ + 1) 111 (3R)-3-THFFAB-MS(Pos); 403(M⁺ + 1) 112 (3S)-3-THF FAB-MS(Pos); 403(M⁺ + 1) 113cyclopent-3-en-1-yl FAB-MS(Pos); 399(M⁺ + 1) 114 oxetan-3-ylFAB-MS(Pos); 389(M⁺ + 1) 115 4-THP FAB-MS(Pos); 417(M⁺ + 1) 116

FAB-MS(Pos); 427(M⁺ + 1) 117 1-Boc-3-pyrr FAB-MS(Pos); 502(M⁺ + 1) 1181-Boc-4-pipe FAB-MS(Pos); 516(M⁺ + 1) 119 1-Boc-azetidin-3-ylFAB-MS(Pos); 488(M⁺ + 1) 120 tBu FAB-MS(Pos); 389(M⁺ + 1) 121 MeO(CH₂)₂—FAB-MS(Pos); 391(M⁺ + 1) 122 CF₃CH(Me)- FAB-MS(Pos); 429(M⁺ + 1) 123

FAB-MS(Pos); 489(M⁺ + 1) 124 HO(CH₂)₃— ESI-MS(Neg); 389(M⁺ − 1) 1253-methylcyclopent-3-en-1yl FAB-MS(Pos); 413(M⁺ + 1)

REFERENCE EXAMPLE 126

Palladium-carbon was added to a solution of the compound of ReferenceExample 105 in trifloroacetic acid, for stirring under hydrogen pressurefor 12 hours, to obtain ethyl9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylate.

FAB-MS(Pos): 387 (M⁺+1)

REFERENCE EXAMPLE 127

The compound of Reference Example 95 was dissolved in methylenechloride, to which trifluoroacetic acid was added, for stirring atambient temperature for 24 hours, to obtain[7-(cyclohexylamino)-3-(ethoxycarbonyl)-6-fluoro-4-oxoquinolin-1(4H)-yl]aceticacid trifluoroacetate.

FAB-MS(Pos): 391 (M⁺+1)

In the same manner as in the process of Reference Example 127, ReferenceExample 128 was produced using the corresponding starting material.

REFERENCE EXAMPLE 128

2-[7-(Cyclohexylamino)-3-(ethoxycarbonyl)-6-fluoro-4-oxoquinolin-1(4H)-yl]propionicacid.

ESI-MS(Pos): 405 (M⁺+1)

REFERENCE EXAMPLE 129

The compound of Reference Example 127 was dissolved in THF, to which1,1′-carbonyldiimidazole was added under ice cooling, for stirring underice cooling for one hour. Then water was added to the mixture, to whichsodium borohydride was added, for stirring at ambient temperature for 4hours, to obtain7-(cyclohexylamino)-6-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 377 (M⁺+1)

In the same manner as in the process of Reference Example 129, ReferenceExample 130 was produced using the corresponding starting material.

REFERENCE EXAMPLE 130

Ethyl7-(cyclohexylamino)-6-fluoro-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 391 (M⁺+1)

REFERENCE EXAMPLE 131

The compound of Reference Example 129 was dissolved in methylenechloride, to which pyridinium p-toluenesulfonate and dihydropyrane weresequentially added under ice cooling, for stirring at ambienttemperature for 3 days, to obtain ethyl7-(cyclohexylamino)-6-fluoro-4-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 461 (M⁺+1)

REFERENCE EXAMPLE 132

The compound of Reference Example 127 was dissolved in THF, to which1,1′-carbonylbis-1H-imidazole was added under ice cooling, for stirringat ambient temperature for 2.5 hours. An aqueous methylamine solutionwas added to the resulting reaction mixture under ice cooling, forstirring at ambient temperature for one hour, to obtain ethyl7-(cyclohexylamino)-6-fluoro-1-[2-(methylamino)-2-oxoethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 404 (M⁺+1)

In the same manner as in the process of Reference Example 132, ReferenceExamples 133 through 134 were produced using the respectivecorresponding starting materials.

REFERENCE EXAMPLE 133

Ethyl7-(cyclohexylamino)-6-fluoro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 473 (M⁺+1)

REFERENCE EXAMPLE 134

Ethyl7-(cyclohexylamino)-6-fluoro-1-(2-morpholin-4-yl-2-oxoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 460 (M⁺+1)

REFERENCE EXAMPLE 135

An aqueous 70% acetic acid solution was added to the compound ofReference Example 110, for stirring at 80° C. for 18 hours, to obtainethyl7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 407 (M⁺+1)

REFERENCE EXAMPLE 136

The compound of Reference Example 135 was dissolved in DMF, to whichmethyl iodide and silver oxide were added for stirring at ambienttemperature for 51 hours, to obtain ethyl7-(cyclohexylamino)-6-fluoro-1-[2-methoxy-1-(methoxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 435 (M⁺+1)

REFERENCE EXAMPLE 137

The compound of Reference Example 129 was dissolved in methylenechloride, to which triethylamine and methanesulfonyl chloride were addedunder ice cooling, for stirring at ambient temperature for 2 hours, toobtain a mesyl compound. The mesyl compound was dissolved in DMF, towhich sodium azide was added for stirring at ambient temperature for 5hours, to obtain an azide compound. The azide compound was dissolved inT{F, to which triphenylphosphine was added, for stirring at 50° C. forone hour. Water was then added for stirring overnight at 80° C. Pyridineand acetic anhydride were added to the resulting reaction mixture, forstirring at ambient temperature for 3 hours, to obtain ethyl1-[2-(acetylamino)ethyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 418 (M⁺+1)

In the same manner as in the process of Reference Example 137, ReferenceExamples 138 through 140 were produced using the respectivecorresponding starting materials.

REFERENCE EXAMPLE 138

Ethyl1-[2-(acetylamino)propyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 432 (M⁺+1)

REFERENCE EXAMPLE 139

Ethyl1-{2-(acetylamino)-1-[(acetylamino)methyl]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 489 (M⁺+1)

REFERENCE EXAMPLE 140

Ethyl1-[2-(acetylamino)-1-methylethyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 432 (M⁺+1)

REFERENCE EXAMPLE 141

The compound of Reference Example 117 was suspended in EtOAc, to which4M HCl-EtOAc solution was added under ice cooling, for stirring as itwas for one hour, overnight at ambient temperature and overnight at 50°C. Insoluble materials therein were filtered and dried. The driedmaterials were suspended in methylene chloride, to which sodium acetate,formaldehyde solution (36%) and sodium triacetoxyborohydride were addedunder ice cooling, for stirring for 45 minutes as the mixture remainedas it was, to obtain ethyl7-(cyclohexylamino)-6-fluoro-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 416 (M⁺+1)

In the same manner as in the process of Reference Example 141, ReferenceExamples 142 and 143 were produced using the respective correspondingstarting materials.

REFERENCE EXAMPLE 142

Ethyl7-(cyclohexylamino)-6-fluoro-1-(1-methylpiperidin-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 430 (M⁺+1)

REFERENCE EXAMPLE 143

Ethyl7-(cyclohexylamino)-6-fluoro-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 402 (M⁺+1)

REFERENCE EXAMPLE 144

5-Methoxy-3,4-dihydro-2H-pyrrole and triethylamine were added to ethyl3-oxo-3-(2,4,5-trifluorophenyl)propanoate, for stirring at 60° C. for 4days, to obtain ethyl3-oxo-2-pyrrolidin-2-ylidene-3-(2,4,5-trifluorophenyl)propanoate.

ESI-MS(Pos): 314 (M⁺+1)

REFERENCE EXAMPLE 145

60% sodium hydride was added to a dioxane solution of the compound ofReference Example 144, for stirring at ambient temperature for one hour,to obtain ethyl7,8-difluoro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate.

ESI-MS(Pos): 294 (M⁺+1)

REFERENCE EXAMPLE 146

Diethylaminosulfur trifluoride was added to a methylene chloridesolution of the compound of Reference Example 130 in at −78° C. Then,the mixture was gradually warmed to ambient temperature over 2 hours, toobtain ethyl7-(cyclohexylamino)-6-fluoro-1-(2-fluoro-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 393 (M⁺+1)

REFERENCE EXAMPLE 147

To a methylene chloride solution of the compound of Reference Example130 were added triethylamine and methanesulfonyl chloride at 0° C., forstirring as it was for one hour, to obtain a mesyl compound. The mesylcompound was dissolved in THF, to which potassium tert-butoxide wasadded for stirring at ambient temperature for 3 hours, to obtain ethyl7-(cyclohexylamino)-6-fluoro-1-isopropenyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 373 (M⁺+1)

REFERENCE EXAMPLE 148

Sodium hydride and methyl iodide were added to a DMF solution of thecompound of Reference Example 137 at 0° C., for stirring for 5 hours, toobtain ethyl1-{2-[acetyl(methyl)amino]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 446 (M⁺+1)

In the same manner as in the process of Reference Example 148, ReferenceExamples 149 was produced using the corresponding starting material.

REFERENCE EXAMPLE 149

Ethyl1-{2-[acetyl(methyl)amino]-1-methylethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 446 (M⁺+1)

REFERENCE EXAMPLE 150

Palladium-carbon and conc. hydrochloric acid were added to a EtOHsolution of the compound of Reference Example 102, for stirring underhydrogen atmosphere for 12 hours, to obtain ethyl8-(cyclohexylamino)-7-fluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate.

ESI-MS(Pos): 387 (M⁺+1)

In the same manner as in the process of Reference Example 150, ReferenceExamples 151 was produced using the corresponding starting material.

REFERENCE EXAMPLE 151

Ethyl9-(cyclohexylamino)-8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-4-carboxylate.

ESI-MS(Pos): 401 (M⁺+1)

REFERENCE EXAMPLE 152

Potassium carbonate and iodocyclopentane were added to a DMF solution ofethyl 6,7-difluoro-4-hydroxycinnoline-3-carboxylate, for stirring at 80°C. for 40 minutes, to obtain ethyl1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate.

FAB-MS(Pos): 323 (M⁺+1)

In the same manner as in the process of Reference Example 152, ReferenceExamples 153 was produced using the corresponding starting material.

REFERENCE EXAMPLE 153

Ethyl1-(1-ethylpropyl)-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate.

FAB-MS(Pos): 325 (M⁺+1)

REFERENCE EXAMPLES 154 AND 155

Ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate was dissolved in aceticanhydride, to which ethyl orthoformate was added at ambient temperature,for stirring at 140° C. for 3 hours and subsequent concentration underreduced pressure. The resulting residue was dissolved in EtOH, to which[2-fluoro-1-(fluoromethyl)ethyl]amine hydrochloride and triethylaminewere added under ice cooling, for stirring at ambient temperature for 30minutes and subsequent concentration under reduced pressure.

Water was added to the resulting residue, for ethyl acetate extraction.The resulting organic layer was washed with aqueous saturated sodiumchloride, dried over anhydrous sodium sulfate and concentrated. Theresulting residue was dissolved in acetonitrile, to which potassiumcarbonate was added at ambient temperature, for stirring at 50° C. for15 hours and additional stirring at 80° C. for 7 hours, to obtain ethyl6,7-difluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate(Reference Example 154) and ethyl6,7-difluoro-1-[1-(fluoromethyl)vinyl]4-oxo-1,4-dihydroquinoline-3-carboxylate(Reference Example 155).

REFERENCE EXAMPLE 154

FAB-MS(Pos): 332 (M⁺+1)

REFERENCE EXAMPLE 155

FAB-MS(Pos): 312 (M⁺+1)

REFERENCE EXAMPLE 156

3-Pentanone, acetic acid and sodium triacetoxyborohydride were added toa 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, for stirring atambient temperature for 14 hours, to obtainN-(1-ethylpropyl)-3,4,5-trifluoroaniline.

EI-MS(Pos): 217 (M⁺+1)

REFERENCE EXAMPLE 157

Diethyl (ethoxymethylene)malonate was added to the compound of ReferenceExample 156, for stirring at 130° C. for 20 hours, to obtain diethyl{[(1-ethylpropyl)(3,4,5-trifluorophenyl)amino]methylene}malonate.

FAB-MS(Pos): 388 (M⁺+1)

REFERENCE EXAMPLE 158

Polyphosphoric acid was added to the compound of Reference Example 157,for stirring at 130° C. for 30 minutes, to obtain ethyl1-(1-ethylpropyl)-5,6,7-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 342 (M⁺+1)

REFERENCE EXAMPLE 159

The compound of Reference Example 88 was added to a toluene suspensionof lithium methoxide, for stirring at ambient temperature for 3 days, toobtain ethyl1-ethyl-6,7-difluoro-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 312 (M⁺+1)

In the same manner as in the process of Reference Example 159, ReferenceExample 160 was produced using the corresponding starting material.

REFERENCE EXAMPLE 160

5-(Benzyloxy)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

ESI-MS(Pos): 481 (M⁺+1)

REFERENCE EXAMPLE 161

An aqueous solution of methylamine was added to a toluene suspension ofthe compound of Reference Example 88, for stirring at 70° C. for 20hours, to obtain ethyl1-ethyl-6,7-difluoro-5-(methylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

ESI-MS(Pos): 311 (M⁺+1)

In the same manner as in the process of Reference Example 161, ReferenceExample 162 was produced using the corresponding starting material.

REFERENCE EXAMPLE 162

Ethyl5-(benzylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 387 (M⁺+1)

REFERENCE EXAMPLE 163

3-Methylcyclopent-3-ene-1-carboxylic acid was dissolved in toluene, towhich tert-butanol, triethylamine and diphenylphosphorylazide weresequentially added for stirring at 90° C. for 3 days, to obtaintert-butyl (3-methylcyclopent-3-en-1-yl)carbamate.

NMR(CDCl₃) δ; 1.44(s,9H), 1.71(brs,3H), 2.02-2.18(m,2H),2.58-2.77(m,2H), 4.27(brs,1H), 4.69(brs,1H), 5.25(brs,1H)

REFERENCE EXAMPLE 164

The compound of Reference Example 163 was dissolved in methylenechloride, to which trifluoroacetic acid was added, for stirring atambient temperature for 4 hours, to obtain3-methylcyclopent-3-ene-1-amine trifluoroacetate. Ethyl3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate was dissolved in aceticanhydride, to which ethyl orthoformate was added, for stirring at 150°C. for 2 hours and subsequent concentration under reduced pressure. Theresulting residue was dissolved in EtOH, to which triethylamine and3-methylcyclopent-3-ene-1-amine trifluoroacetate were sequentially addedunder ice cooling, for stirring under ice cooling for 18 hours, toobtain ethyl2-(2-chloro-4,5-difluorobenzoyl)-3-[(3-methylcyclopenta-3-en-1-yl)amino]acrylate.The resulting compound was dissolved in 1,4-dioxane, to which sodiumhydride was added, for stirring at 50° C. for 3 hours, to obtain ethyl6,7-difluoro-1-(3-methylcyclopenta-3-en-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 334 (M⁺+1)

REFERENCE EXAMPLE 165

The compound of Reference Example 162 was dissolved in EtOH-acetic acid,to which palladium-carbon (10%) was added, for stirring under hydrogenatmosphere for 3 hours, to obtain ethyl5-amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 297 (M⁺+1)

REFERENCE EXAMPLE 166

3-Pentanone and p-toluenesulfonic acid monohydrate were added to abenzene solution of ethyl7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate,for stirring under reflux under heating for 34 hours, to obtain ethyl7-(cyclohexylamino)-1-(2,2-diethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS(Pos): 475 (M⁺+1)

REFERENCE EXAMPLE 167

The compound of Reference Example 92 was dissolved in EtOH-THF, to which2M aqueous NaOH was added, for stirring at ambient temperature for 12hours, to obtain7-(cyclohexylamino)-1-ethyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

In the same manner as in the process of Reference Example 167, ReferenceExamples 168 through 214 as shown in Tables 12 through 15 were producedusing the respective corresponding starting materials. TABLE 12

Rf R¹ R Data 167 F Et FAB-MS(Pos); 351(M⁺ + 1) 168 H(1,3-dioxolan-2-yl)-CH₂— FAB-MS(Pos); 391(M⁺ + 1) 169 H2,2-diMe-1,3-dioxan-5-yl FAB-MS(Pos); 419(M⁺ + 1) 170 H 3-THFFAB-MS(Pos); 375(M⁺ + 1) 171 H (3R)-3-THF FAB-MS(Pos); 375(M⁺ + 1) 172 H(3S)-3-THF FAB-MS(Pos); 375(M⁺ + 1) 173 H cyclopent-3-en-1-ylFAB-MS(Pos); 371(M⁺ + 1) 174 H oxetan-3-yl FAB-MS(Pos); 361(M⁺ + 1) 175H 4-THP FAB-MS(Pos); 389(M⁺ + 1) 176 H

FAB-MS(Pos); 399(M⁺ + 1) 177 H 1-Boc-3-pyrr FAB-MS(Pos); 474(M⁺ + 1) 178H 1-Boc-4-pipe FAB-MS(Pos); 488(M⁺ + 1) 179 H tBu FAB-MS(Pos);361(M⁺ + 1) 180 H MeO(CH₂)₂— FAB-MS(Pos); 363(M⁺ + 1) 181 H CF₃CH(Me)CH—FAB-MS(Pos); 401(M⁺ + 1) 182 H

FAB-MS(Pos); 461(M⁺ + 1) 183 H 2-THP-O—(CH₂)₂— FAB-MS(Pos); 433(M⁺ + 1)184 H MeNH(CO)CH₂— ESI-MS(Pos); 376(M⁺ + 1) 185 H (4-Me-1-pipe)(CO)CH₂—ESI-MS(Pos); 445(M⁺ + 1) 186 H (4-mor)(CO)CH₂— FAB-MS(Pos); 432(M⁺ + 1)187 H (MeO CH₂)₂CH— FAB-MS(Pos); 407(M⁺ + 1) 188 H AcNH(CH₂)₂—FAB-MS(Pos); 390(M⁺ + 1) 189 H AcNH(CH₂)₃— FAB-MS(Pos); 404(M⁺ + 1) 190H (AcNHCH₂)₂CH— FAB-MS(Pos); 461(M⁺ + 1) 191 H 1-Me-3-pyrr FAB-MS(Pos);388(M⁺ + 1) 192 H 1-Me-4-pipe FAB-MS(Pos); 402(M⁺ + 1) 193 H1-Me-azetidin-3-yl FAB-MS(Pos); 374(M⁺ + 1) 194 OMe Et ESI-MS(Pos);363(M⁺ + 1) 195 H FCH₂CH(Me)- FAB-MS(Pos); 365(M⁺ + 1) 196 H isopropenylFAB-MS(Pos); 345(M⁺ + 1) 197 H AcNHCH₂CH(Me)- FAB-MS(Pos); 404(M⁺ + 1)198 H AcN(Me)(CH₂)₂— FAB-MS(Pos); 418(M⁺ + 1) 199 H AcN(Me)CH₂CH(Me)-FAB-MS(Pos); 418(M⁺ + 1) 200 NH(cHex) Et FAB-MS(Pos); 351(M⁺ + 1) 201NHMe Et ESI-MS(Pos); 283(M⁺ + 1) 202 H 3-methylcyclopent-3-en-lylFAB-MS(Pos); 385(M⁺ + 1) 203 H 2-THP-OCH₂CH(Me)- FAB-MS(Pos);447(M⁺ + 1) 204 H 2,2-diethyl-1,3-dioxan-5-yl FAB-MS(Pos); 447(M⁺ + 1)205 F (Et)₂CH— FAB-MS(Pos); 393(M⁺ + 1) 206 AcN(Me)- (Et)₂CH—ESI-MS(Pos); 446(M⁺ + 1)

TABLE 13

Rf R Data 207 NH2 FAB-MS(Pos); 269(M⁺ + 1) 208 NHMe ESI-MS(Pos);283(M⁺ + 1) 209 NH(cHex) FAB-MS(Pos); 351(M⁺ + 1)

TABLE 14

Rf R R Data 210 H H FAB-MS(Pos); 345(M⁺ + 1) 211 Me H FAB-MS(Pos);359(M⁺ + 1) 212 CH₂═ FAB-MS(Pos); 357(M⁺ + 1)

TABLE 15

Rf R Data 213 cPen FAB-MS(Pos); 374(M⁺ + 1) 214 (Et)₂CH— FAB-MS(Pos);376(M⁺ + 1)

REFERENCE EXAMPLE 215

Aqueous LiOH was added to a EtOH-THF solution of the compound ofReference Example 104, for stirring at 60° C. for 24 hours and at 80° C.for 24 hours, to obtain7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

FAB-MS(Pos): 387 (M⁺+1)

In the same manner as in the process of Reference Example 215, ReferenceExamples 216 through 220 were produced using the respectivecorresponding starting materials.

REFERENCE EXAMPLE 216

9-(Cyclohexylamino)-8-fluoro-6-oxo-6H-pyrido[1,2-a]quinoline-5-carboxylicacid

FAB-MS(Pos): 355 (M⁺+1)

REFERENCE EXAMPLE 217

Ethyl[7-(cyclohexylamino)-6-fluoro-1-isopropyl4-oxo-1,4-dihydro-1,8-naphthylidin-3-yl]carboxylicacid

FAB-MS(Pos): 348 (M⁺+1)

REFERENCE EXAMPLE 218

Ethyl9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylicacid

FAB-MS(Neg): 357 (M⁺−1)

REFERENCE EXAMPLE 219

9-(Cyclohexylamino)-8-fluoro-2-methylene-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoquinoline-5-carboxylicacid

FAB-MS(Pos): 371 (M⁺+1)

REFERENCE EXAMPLE 220

9-(Cyclohexylamino)-8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[-1,2-a]quinoline-5-carboxylicacid

FAB-MS(Pos): 373 (M⁺+1)

REFERENCE EXAMPLE 221

An aqueous solution of sodium nitrate was added dropwise to an aqueoushydrochloric acid solution of 3,4-difluoroaniline under ice cooling, forstirring at the same temperature for 1.5 hours. The resulting reactionmixture was added dropwise to an aqueous EtOH solution of ethylcyanoacetate and sodium acetate as prepared in a separate reactionflask, for stirring at ambient temperature for 2 hours, to obtain ethylcyano[(3,4-difluorophenyl)diazenyl]acetate.

FAB-MS(Pos): 254 (M⁺+1)

REFERENCE EXAMPLE 222

The compound of Reference Example 221 was suspended in acetonitrile, towhich ethyl iodide and potassium carbonate were added for stirring at50° C. for 7 days, to obtain ethyl2-cyano[(3,4-difluorophenyl)(ethyl)hydrazono]acetate.

FAB-MS(Pos): 282 (M⁺+1)

REFERENCE EXAMPLE 223

The compound of Reference Example 222 was suspended in EtOH, to whichaqueous NaOH was added under ice cooling, for stirring at ambienttemperature for 2 hours, to obtain2-cyano[(3,4-difluorophenyl)(ethyl)hydrazono]acetic acid.

FAB-MS(Pos): 254 (M⁺+1)

REFERENCE EXAMPLE 224

The compound of Reference Example 223 was suspended in toluene, to whichthionyl chloride was added, for stirring at 90° C. for 1.5 hours andsubsequent concentration under reduced pressure. The resulting residuewas azeotropically evaporated with toluene. Hexane was added to theresidue and the resulting solid was filtered. The solid was dissolved indichloroethane, to which aluminium chloride was added for stirring at55° C. for 24 hours and reflux for another 23 hours, to obtain1-ethyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carbonitrile.

FAB-MS(Pos): 236 (M⁺+1)

REFERENCE EXAMPLE 225

The compound of Reference Example 224 was dissolved in DMSO, to whichcyclohexylamine was added, for stirring at 80° C. for 3 hours, to obtain7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnoline-3-carbonitrile.

FAB-MS(Pos): 315 (M⁺+1)

REFERENCE EXAMPLE 226

The compound of Reference Example 225 was dissolved in acetic acid, towhich aqueous HCl was added, for stirring at 120° C. for 2 days, toobtain7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinrioline-3-carboxylicacid.

FAB-MS(Pos): 334 (M⁺+1)

REFERENCE EXAMPLE 227

DMF and N-chlorosuccinimide were added to the compound of ReferenceExample 40, for stirring at 100° C. for 14 hours, to obtain8-chloro-7-(cyclohexylamino)-l-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

FAB-MS(Pos): 367 (M⁺+1)

REFERENCE EXAMPLE 228

Cyclohexylamine was added to a DMSO solution of the compound ofReference Example 153, for stirring at 80° C. for 14 hours. After thereaction mixture was cooled to ambient temperature, water and saturatedaqueous ammonium chloride were added for chloroform extraction. Theresulting organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate and concentrated. Theresulting residue was dissolved in ethanol, to which aqueous 1N sodiumhydroxide solution was added, for stirring at ambient temperature for 2hours, to obtain7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylicacid.

FAB-MS(Pos): 376 (M⁺+1)

REFERENCE EXAMPLE 229

Water and conc. hydrochloric acid were added to an acetic acid solutionof the compound of Reference Example 154, for stirring at 100° C. for 5hours, to obtain6,7-difluoro-1-[2-fluoro-1-(fluoromethyl)ethyl)-4-oxo-1,4-fihydroquinoline-3-carboxylicacid.

FAB-MS(Pos): 304 (M⁺+1)

In the same manner as in the process of Reference Example 229, ReferenceExample 230 was produced using the corresponding starting material.

REFERENCE EXAMPLE 230

6,7-Difluoro-1-[1-(fluoromethyl)vinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

FAB-MS(Pos): 284 (M⁺+1)

REFERENCE EXAMPLE 231

The compound of Reference Example 130 was dissolved in methylenechloride, to which pyridinium p-toluenesulfonate and dihydropyrane weresequentially added for overnight stirring at ambient temperature, toobtain ethyl7-(cyclohexylamino)-6-fluoro-1-[1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.The resulting compound was suspended in EtOH-THF, to which 1M aqueousNaOH was added for overnight stirring, to obtain7-(cyclohexylamino)-6-fluoro-1-[1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

FAB-MS(Pos): 447 (M⁺+1)

REFERENCE EXAMPLE 232

The compound of Reference Example 40 was suspended in DMF, to which1,1′-carbonylbis-1H-imidazole was added at ambient temperature, forstirring at 100° C. for 24 hours, to obtain7-(cyclohexylamino)-1-ethyl-6-fluoro-3-(1H-imidazol-1-ylcarbonyl)quinolin-4(1H)-one.

NMR(CDCl₃) δ; 1.25-1.53(m,5H), 1.59(t,J=7.6 Hz,3H), 1.65-1.76(m,1H),1.80-1.90(m,2H), 2.05-2.15(m,2H), 3.34-3.45(m,1H), 4.22(q,J=7.6 Hz,2H),4.57-4.66(m,1H), 6.44(d,J=6.4 Hz,1H), 7.04-7.05(m,1H), 7.51-7.53(m,1H),7.99(d,J=12.0 Hz,1H), 8.12(s,1H), 8.15-8.16(m, 1H).

REFERENCE EXAMPLE 233

By the same method described below in Example 16, tert-butyl{[(6,7-difluoro-1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetatewas obtained from the compound of Reference Example 30.

FAB-MS(Pos): 367 (M+1)

In the same manner as in Reference Example 233, Reference Example 234was produced using the corresponding starting material.

REFERENCE EXAMPLE 234

Ethyl{[(5-amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetate

FAB-MS(Pos): 354 (M⁺+1)

REFERENCE EXAMPLE 235

Acetic anhydride was added to the compound of Reference Example 234, forstirring at 120° C. for 4 hours, to obtain ethyl({[5-(acetylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

FAB-MS(Pos): 396 (M⁺+1)

In the same manner as in Reference Example 235, Reference Example 236was produced using the corresponding starting material.

REFERENCE EXAMPLE 236

Ethyl[5-(acetylmethylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl]carboxylicacid

ESI-MS(Pos): 395 (M⁺+1)

REFERENCE EXAMPLE 237

(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl)phosphonic acid wassuspended in benzene, to which benzyl N,N′-dicyclohexylimide carbamatewas added, for stirring under reflux conditions for 4 hours, to obtaindibenzyl (2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl)phosphonate.

FAB-MS(Pos): 528 (M⁺+1)

REFERENCE EXAMPLE 238

The compound of Reference Example 237 was dissolved in DMF, to whichdiisopropylethylamine was added, for stirring at ambient temperature for2 days, to obtain dibenzyl (2-aminoethyl)phosphonate. Further, oxalicacid was added to the resulting phosphonate, to obtain dibenzyl(2-aminoethyl)phosphonate oxalate.

FAB-MS(Pos): 306 (M⁺+1)

REFERENCE EXAMPLE 239

Hydrazine monohydrate was added to a methylene chloride solution ofdiethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate,for stirring at ambient temperature for one hour, to obtain diethyl(2-amino-1,1-difluoroethyl)phosphonate.

ESI-MS(Pos): 218 (M⁺+1)

REFERENCE EXAMPLE 240

Diethyl pyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, towhich platinum oxide was added, for stirring under 3.4 kgf/cm² hydrogenfor 120 hours, to obtain diethyl piperidin-3-ylphosphonate.

ESI-MS(Pos): 222 (M⁺+1)

In the same manner as in the process of Reference Example 240, ReferenceExample 241 was produced using the corresponding starting material.

REFERENCE EXAMPLE 241

Diethyl (piperidin-2-ylmethyl)phosphonate

FAB-MS(Pos): 236 (M⁺+1)

REFERENCE EXAMPLE 242

Palladium-carbon (10%) was added to a solution of benzyl ((3aRS, 4SR,6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamatein EtOH, for stirring overnight under hydrogen atmosphere, to obtain(3aRS, 4SR, 6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine.

FAB-MS(Pos): 288 (M⁺+1)

REFERENCE EXAMPLE 243

Platinum oxide and conc.HCl were added to a solution of diethyl(1-cyano-2-phenylethyl)phosphonate in EtOH, for overnight stirring underhydrogen atmosphere, to obtain diethyl[2-amino-1-(cyclohexylmethyl)ethyl]phosphonate.

FAB-MS(Pos): 278 (M⁺+1)

EXAMPLE 1

400 mg of the compound of Reference Example 59 was suspended in 5.0 mlof DMF, to which 350 mg of 1,1′-carbonylbis-1H-imidazole was added atambient temperature, for stirring at 100° C. for 20 hours. 0.2 ml oftriethylamine and 180 mg of glycine ethyl ester hydrochloride were addedsequentially to the resulting reaction mixture under ice cooling, forstirring at ambient temperature for another 5 hours. The reactionmixture was concentrated under reduced pressure, to which water wasadded for chloroform extraction. The resulting organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting solid was recrystallized from EtOH, to obtain408 mg of ethyl({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 2

300 mg of the compound of Reference Example 232 was dissolved in 5.0 mlof DMF, to which 0.2 ml of triethylamine and 120 mg of glycine ethylester hydrochloride were added sequentially to the resulting reactionmixture under ice cooling, for stirring at ambient temperature for 4.5hours. The reaction mixture was concentrated under reduced pressure, towhich water was added for chloroform extraction. The resulting organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting solid wasrecrystallized from EtOH, to obtain 219 mg of ethyl({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 3

The compound of Reference Example 232 was dissolved in 3.0 ml of DMF, towhich 150 mg of O-trimesylsilylhydroxylamine was added under icecooling, for stirring at 50° C. for 5.5 hours. The reaction mixture wasconcentrated under reduced pressure, to which 5.0 ml of MeOH was added.Subsequently, 4.0 ml of aqueous 1M HCl was added under ice cooling, forstirring at ambient temperature for 2 hours and at 50° C. for 2.5 hours.The resulting mixture was left to stand for cooling to ambienttemperature, to obtain the resulting solid, which was then washed withEtOAc and then recrystallized from aqueous 80% acetic acid, to obtain141 mg of7-(cyclohexylamino)-1-ethyl-6-fluoro-N-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamide.

EXAMPLE 4

300 mg of the compound of Example 56 was suspended in 5.0 ml of EtOH, towhich 1.0 ml of aqueous 3M HCl was added under ice cooling, for stirringat 50° C. for 22 hours. The reaction mixture was concentrated underreduced pressure, to which water was added. The resulting mixture wasneutralized with aqueous 1M NaOH, for 10% MeOH-chloroform extraction.The resulting organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting solidwas washed with EtOH, to obtain 230 mg of7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-N-[(1RS, 2RS, 3RS,4SR)-2,3,4-trihydroxycyclopentyl]-1,4-dihydroquinoline-3-carboxamide.

EXAMPLE 5

360 mg of the compound of Example 51 was dissolved in 5.0 ml ofmethylene chloride, to which 2.0 ml of trifluoroacetic acid was addedunder ice cooling, for stirring at ambient temperature for 15 hours. Thereaction mixture was concentrated under reduced pressure, to which waterwas added for chloroform extraction. The resulting organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The resulting solid was washed from diisopropyl ether,to obtain 282 mg of(4S)-4-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-5-[4-(ethoxycarbonyl)piperazin-1-yl]-5-oxopentanoicacid.

EXAMPLE 6

300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, towhich 0.8 ml of aqueous 1M NaOH was added under ice cooling, forstirring at ambient temperature for 25 hours. Water was added to thereaction mixture, which was neutralized with aqueous 1M HCl. Theresulting solid was filtered and washed with EtOH, to obtain 263 mg of({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)aceticacid.

EXAMPLE 7

2.23 ml of bromotrimethylsilane (TMSBr) was gradually added to asolution of 1.106 g of the compound of Example 44 in 20 ml of chloroformunder ice cooling, for stirring under ice cooling for 30 minutes andthen at ambient temperature for 6 hours. The reaction mixture wasconcentrated under reduced pressure, to which 15 ml of MeOH was added.Again, the resulting mixture was concentrated under reduced pressure, towhich ether and a small amount of MeOH were added. The generatedinsoluble materials were filtered and recovered. 10 ml of aqueous 1MNaOH, MeOH and water were added to the insoluble materials, to filteroff the insoluble matters. The precipitate resulting from the additionof 1 ml of aqueous 1M HCl to the filtrate was filtered. The precipitatewas washed with 80% EtOH, to obtain 841 mg of[2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonicacid.

EXAMPLE 8

250 mg of the compound of Example 374 was suspended in 2.0 ml of EtOAc,to which 2.0 ml of 4M HCl-EtOAc solution was added under ice cooling,for stirring at ambient temperature for 4 days. The generated solid wasfiltered and washed with EtOAc, to obtain 210 mg of({[1-ethyl-6-fluoro-4-oxo-(7-piperidin-4-ylamino)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetatehydrochloride.

EXAMPLE 9

300 mg of the compound of Example 163 was suspended in 5.0 ml of THF, towhich 200 mg of 1,1′-carbonylbis-1H-imidazole was added under icecooling, for stirring at ambient temperature for 17 hours. 1.0 ml ofaqueous 28% ammonia was added to the resulting reaction mixture underice cooling, for stirring at ambient temperature for another 1.5 hours.The reaction mixture was concentrated under reduced pressure, to whichwater was added for chloroform extraction. The resulting organic layerwas dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure. The resulting solid was recrystallized from EtOH, toobtain 214 mg ofN-(4-amino-4-oxobutyl)-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-carboxamide.

EXAMPLE 10

210 mg of the compound of Example 161 was suspended in 5.0 ml of DMF, towhich 0.1 ml of ethoxycarbonylpiperazine, 130 mg of WSC.HCl and 100 mgof 1-hydroxybenzotriazole were added sequentially to the resultingreaction mixture under ice cooling, for stirring at ambient temperaturefor 17 hours. The reaction mixture was concentrated under reducedpressure, to which water was added for chloroform extraction. Theresulting organic layer was washed sequentially with aqueous saturatedNaHCO₃ and aqueous saturated sodium chloride, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure. Theresulting solid was washed with EtOH, to obtain 228 mg of ethyl4-[({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetyl]piperazine-1-carboxylate.

EXAMPLE 11

530 mg of the compound of Example 196 was suspended in a mixed solventof 10 ml of acetone and 3.0 ml of water, to which 0.30 g ofN-methylmorpholine-N-oxide and 2.0 ml of OsO₄ (2.5 wt % in BuOH) weresequentially added at ambient temperature, for stirring at ambienttemperature for one week. Water was added to the reaction mixture, towhich 2.0 g of sodium thiosulfate was added at ambient temperature, forovernight stirring at ambient temperature. Insoluble matters in thereaction mixture were filtered off, while the resulting filtrate wasconcentrated under reduced pressure. The resulting solid was washed withwater, to obtain 190 mg of ethyl({[7-(cyclohexylamino)-1-(2,3-dihydroxypropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 12

423 mg of the compound of Example 72 was suspended in 5 ml of chloroformand 5 ml of MeOH, to which 126 mg of LiOH.H₂O was added, for stirring atambient temperature for 30 minutes. 1.17 g ofmethyl-1-bromo-1-deoxy-2,3,4-tri-o-acetyl-α-D-glucopyranoside uronatewas added to the reaction mixture, for stirring at ambient temperaturefor one hour. Further, 126 mg of LiOH.H₂O and 1.17 g ofmethyl-1-bromo-1-deoxy-2,3,4-tri-o-acetyl-α-D-glucopyranoside uronatewere added, for stirring at ambient temperature for 6 hours. 15 ml ofwater, 5 ml of MeOH and 1.0 g of sodium carbonate were added to thereaction mixture, for stirring at ambient temperature for 1.5 hours.Additionally, 30 ml of water, 220 ml of MeOH and 1.0 g of sodiumcarbonate were added, for stirring at ambient temperature for 30minutes. The resulting mixture was neutralized with acetic acid andstirred at ambient temperature for 12 hours. After the resultinginsoluble matters were filtered off, water was added to the resultingfiltrate, which was then washed with chloroform. The resulting aqueoussolution was concentrated under reduced pressure. The residue waspurified by ODS column chromatography, to obtain 168 mg of3-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)phenylβ-D-glucopyranoside uronic acid.

EXAMPLE 13

0.20 g of the compound of Reference Example 233 was dissolved in 5.0 mlof DMSO, to which 2.0 ml of cyclohexylmethylamine was added at ambienttemperature, for stirring at 80° C. for 19 hours. Water was added to theresulting reaction mixture, for chloroform extraction. The resultingorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography, to obtain 0.23 g of tert-butyl[({7-[(cyclohexylmethyl)amino]-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetate.

0.23 g of the tert-butyl ester compound was dissolved in 5.0 ml ofmethylene chloride, to which 2.0 ml of trifluoroacetic acid was addedunder ice cooling, for stirring at ambient temperature for 6 hours. Thereaction mixture was concentrated under reduced pressure, to which waterwas added. The generated solid was filtered, to obtain 102 mg of[({7-[(cyclohexylmethyl)amino]-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]aceticacid.

EXAMPLE 14

89 mg of sodium acetate, 55 μl of formaldehyde solution (37%), and 177mg of sodium triacetoxyborohydride were added to a suspension of 253 mgof the compound of Example 210 in 10 ml of THF, for stirring at ambienttemperature for 3 hours. Aqueous saturated NaHCO₃ was added forchloroform extraction. The resulting extract was washed with aqueoussaturated sodium chloride. The resulting organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography, to obtain 146 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(1-methylpyrrolidin-3-yl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 15

0.45 g of the compound of Example 412 was dissolved in 10 ml ofmethylene chloride, to which 1.0 ml of bromotrimethylsilane was addedunder ice cooling, for stirring at ambient temperature for 3 days. Theresulting reaction mixture was concentrated under reduced pressure, towhich MeOH was added, for stirring at ambient temperature for 1.5 hours.The reaction mixture was concentrated under reduced pressure, to whichEtOH was added, to filter the solid, to obtain 344 mg of[2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonicacid hydrobromide.

EXAMPLE 16

The compound of Reference Example 75 was suspended in 20 ml, to which149 μl of triethylamine and 177 μl of isobutyl chloroformate were addedunder ice cooling. After the mixture was stirred as it was for one hour,149 μl of triethylamine and 138 mg of glycine ethyl ester hydrochloridewere added, for stirring at ambient temperature for 12 hours. Aqueoussaturated NH₄Cl was added for chloroform extraction. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography,and washed with EtOAc, to obtain 227 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 17

0.51 g of the compound of Example 200 was dissolved in 5.0 ml ofmethylene chloride, to which 0.5 ml of triethylamine and 0.2 ml ofmethanesulfonyl chloride were added sequentially under ice cooling, forstirring under ice cooling for 30 minutes. Water was added to theresulting solution for chloroform extraction. The resulting organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure, to obtain a mesyl compound. The resulting mesylcompound was dissolved in 10 ml of DMF, to which 0.10 g of sodium azidewas added under ice cooling, for stirring at ambient temperature for 20hours. Water was added to the resulting reaction mixture for chloroformextraction. The resulting organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure, to obtain anazide compound. The resulting azide compound was dissolved in 10 ml ofTHF, to which 0.40 g of triphenylphosphine was added at ambienttemperature, for stirring at 50° C. for one hour. 2.0 ml of water wasadded to the resulting reaction mixture for stirring at 80° C. for 3.5hours. The reaction mixture was left to stand for cooling, to which 0.30g of di-tert-butyl dicarbonate was added under ice cooling, for stirringat ambient temperature for 27 hours. Water was added to the reactionmixture, for chloroform extraction. The resulting organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography, to obtain 494 mg of ethyl{[(1-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetate.

EXAMPLE 18

407 mg of the compound of Example 589 was dissolved in 5 ml of MeOH, towhich 30 mg of palladium-carbon (10%) was added, for stirring underhydrogen atmosphere for 3 hours. After 1.15 ml of aqueous 1M NaOH wasadded to the reaction mixture, the resulting insoluble matters werefiltered off through Celite. Aqueous 1.15 ml of 1M HCl was added to thefiltrate and the resulting precipitate was filtered and washed withwater, to obtain 220 mg of[2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonicacid.

EXAMPLE 19

415 mg of the compound of Example 200 was suspended in 5 ml of methylenechloride, to which 400 μl of triethylamine and 111 μl of methanesulfonylchloride were added under ice cooling, for stirring at ambienttemperature for 10 minutes. Water and aqueous saturated sodium chloridewere added to the reaction mixture, for chloroform extraction. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was dissolvedin 5 ml of DMF, to which 948 μl of piperidine was added, for stirring at70° C. for 23 hours. The reaction mixture was cooled to ambienttemperature, to which water was added for chloroform extraction. Theresulting organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography, to obtain 202 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(2-piperidin-1-ylethyl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 20

149 mg of the compound of Example 31 was suspended in 5 ml ofchloroform, to which 75 μl of triethylamine was added under ice cooling.Then 30 μl of acetyl chloride was added. After overnight stirring atambient temperature, water was added for chloroform extraction and theresulting extract was washed with aqueous saturated sodium chloride. Theresulting organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography, to obtain 167 mg of ethyl({[1-(1-acetylpyrrolidin-3-yl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 21

734 mg of the compound of Example 200 was suspended in 10 ml ofmethylene chloride, to which 708 μl of triethylamine and 197 μl ofmethanesulfonyl chloride were added under ice cooling, for stirring atambient temperature for 15 minutes. Water and aqueous saturated sodiumchloride were added to the reaction mixture, for chloroform extraction.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was dissolvedin 10 ml of DMSO, to which 100 mg of sodium cyanide was added, forstirring at 70° C. for 24 hours. Water and saturated aqueous sodiumchloride were added to the reaction mixture for chloroform extraction.The resulting organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography, to obtain 354 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 22

Aqueous 70% acetic acid was added to 146 mg of the compound of Example18, for stirring at, 60° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure and azeotropically evaporated withEtOH. The resulting residue was crystallized from EtOH-water, to obtain96 mg of ethyl{2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonicacid.

EXAMPLE 23

374 mg of methyl(2R)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-3-pyridin-3-ylpropanoatewas suspended in 4 ml of EtOAc, to which 2 ml of 0.5M HCl EtOAc solutionwas added, for stirring for 30 minutes. Subsequently, the resultingprecipitate was filtered, to obtain 156 mg of methyl(2R)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-3-pyridin-3-ylpropanoatehydrochloride.

EXAMPLE 24

0.5 ml of aqueous 2M NaOH was added to 11 mg of the compound of Example44, for stirring at 100° C. for 30 minutes. 0.1 ml of 2-propanol wasadded, for stirring at 100° C. for 12 hours, to which 1.1 ml of aqueous1M HCl was added. The generated precipitate was filtered and washed withdiethyl ether, to obtain 7 mg of ethyl hydrogen[2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonate.

EXAMPLE 25

148 mg of the compound of Example 31 was suspended in 5 ml ofacetonitrile, to which 67 mg of potassium carbonate, 46 μl of benzylbromide and 5 ml of DMF were added for overnight stirring. Water wasadded, for chloroform extraction and rinsing with aqueous saturatedsodium chloride. The resulting organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography, to obtain174 mg of Ethyl({[1-(1-benzylpyrrolidin-3-yl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 26

183 mg of the compound of Example 220 was suspended in 20 ml ofchloroform, to which 1.35 ml of bromotrimethylsilane was added under icecooling, for stirring at ambient temperature for 24 hours. 1.35 ml ofbromotrimethylsilane was added, for stirring for 3 days, to which EtOHwas added. After the solvent was distilled off under reduced pressure,water and aqueous saturated NaHCO₃ were added to filter insolublematerials. Aqueous saturated NaHCO₃ was added to the insolublematerials, for chloroform extraction. The resulting extract was washedwith aqueous 1M HCl, aqueous saturated NaHCO₃ and aqueous saturatedsodium chloride. The resulting organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography, to obtain54 mg of ethyl [({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(1RS, 2SR, 3RS,4SR)-2,3,4-trihydroxycyclopentyldihydroquinolin-3-yl}carbonyl)amino]acetate.

EXAMPLE 27

10 ml of acetonitrile, 720 μl of 1,8-diazabicyclo[5.4.0]-7-undecene and575 μl of chloromethyl pivalate were added to 743 mg of the compound ofExample 15, 226 mg of tetrabutylammonium hydrogensulfate and 102 mg ofsodium iodide, for stirring at 75° C. for 65 hours. Water was added, forEtOAc extraction. The resulting extract was washed with water, saturatedaqueous NaHCO₃, and aqueous saturated sodium chloride. The resultingorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography and washed with diethyl ether, to obtain378 mg of bis{[(2,2-dimethylpropanoyl)oxy]methyl}[2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonate.

EXAMPLE 28

273 mg of the compound of Example 544 was suspended in 10 ml of THF, towhich 1.2 ml of aqueous 1M LiOH was added for stirring at ambienttemperature for 2 days, at 50° C. for 3 hours and at 60° C. for 20hours. After the solvent was distilled off under reduced pressure,aqueous 1M HCl was added and the generated precipitate was filtered, toobtain 270 mg of2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-2-methylpropionicacid.

EXAMPLE 29

148 mg of the compound of Example 31 was suspended in 5 ml ofchloroform, to which 75 μl of triethylamine was added. The resultingmixture was cooled to −45° C., to which 32 μl of methanesulfonylchloride was added. The mixture was gradually warmed and stirredovernight at ambient temperature. Then, water was added to the resultingmixture, for chloroform extraction and washing with aqueous saturatedsodium chloride. The resulting organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography, to obtain138 mg of ethyl[({7-(cyclohexylamino)-6-fluoro-1-[1-(methylsulfonyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetate.

EXAMPLE 30

0.40 g, of the compound of Example 17 was suspended in 5.0 ml of EtOH,to which 1.1 ml of aqueous 1M NaOH was added under ice cooling, forstirring at ambient temperature for 25 hours.

The resulting reaction mixture was concentrated under reduced pressure.The resulting residue was dissolved in 20 ml of water, to which 3.0 mlof conc. hydrochloric acid was added under ice cooling, for stirring at50° C. for 6 hours. The mixture was left to stand for cooling to ambienttemperature. The generated solid was filtered, to obtain 0.15 g of({[1-(2-aminoethyl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)aceticacid hydrochloride.

EXAMPLE 31

Aqueous saturated NaHCO₃, water and EtOH were added to 1 g of thecompound of Example 210, for chloroform extraction. The resultingorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure, to obtain 750 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 32

2 ml of aqueous 6M HCl was added to 50 mg of the compound of Example241, for stirring at 80° C. for 1.5 hours. 2 ml of aqueous 6M HCl wasadded to the resulting mixture, for stirring at 80° C. for one hour.After the solvent was distilled off under reduced pressure, water wasadded to the resulting residue, to filter insoluble materials. Thematerials were recrystallization from EtOH, to obtain 18 mg of[({7-(cyclohexylamino)-6-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]-4-oxodihydroquinolin-3-yl}carbonyl)amino]acetic acid was obtained.

EXAMPLE 33

52 mg of the compound of Example 348 was suspended in 1 ml of DMSO, towhich 46 μl of triethylamine and 165 μl of a THF solution of 2.0 Mdimethylamine were added, for stirring at 100° C. for 24 hours. Waterwas added and the generated precipitate was filtered. The precipitatewas dissolved in ethyl acetate, and washed with water, saturated NH₄Claqand aqueous saturated sodium chloride. The resulting organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography, to obtain 43 mg of ethyl({[7-(cyclohexylamino)-5-(dimethylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

EXAMPLE 34

53 mg of the compound of Reference Example 235 was dissolved in 1.5 mlof DMSO, to which 31 μl of cyclohexylamine was added at ambienttemperature, for stirring at 80° C. for 13 hours and at 100° C. for 10hours. Water was added to the reaction mixture, and the generatedprecipitate was filtered and washed with water. The precipitate waspurified by silica gel chromatography, to obtain 51 mg of ethyl({[5-(acetylamino)-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.

The structures and physical data of the compounds of the Examples areshown below in Tables 16 through 41. TABLE 16

Ex Syn R Data 2 2 EtO₂CCH₂—NH— FAB-MS(Pos); 418(M⁺ + 1) 3 3 HO—NH—FAB-MS(Pos); 348(M⁺ + 1) 4 4 (1RS,2SR,3RS,4SR)-2,3,4-triHO-cPen-NH—FAB-MS(Pos); 448(M⁺ + 1) 5 5

FAB-MS(Pos); 602(M⁺ + 1) 7 7 (HO)₂(O)P—(CH₂)₂—NH— FAB-MS(Pos);440(M⁺ + 1) 9 9 H₂NOC(CH₂)₃—NH— FAB-MS(Pos); 417(M⁺ + 1) 10 10(4-EtO₂C-1-pipe)-COCH₂—NH— FAB-MS(Pos); 530(M⁺ + 1) 12 12

FAB-MS(Pos); 600(M⁺ + 1) 24 24 (HO)(EtO)(O)P—(CH₂)₂NH— FAB-MS(Pos);468(M⁺ + 1) 35 1 H₂N— FAB-MS(Pos); 332(M⁺ + 1) 36 1 MeNH— FAB-MS(Pos);346(M⁺ + 1) 37 1 Me₂N— FAB-MS(Pos); 360(M⁺ + 1) 38 1 BocHNNH—FAB-MS(Pos); 447(M⁺ + 1) 39 1 Ph-NH— FAB-MS(Pos); 408(M⁺ + 1) 40 1H₂NC(═NH)—NH— FAB-MS(Pos); 374(M⁺ + 1), Sal HCl 41 1 tBuO—NH—FAB-MS(Pos); 404(M⁺ + 1) 42 1 2-MeO₂C-1-pyrr FAB-MS(Pos); 444(M⁺ + 1) 431 Me₂NOCCH(tBuO₂C(CH₂)₂)—NH— FAB-MS(Pos); 545(M⁺ + 1) 44 1(EtO)₂(O)P(CH₂)₂—NH— FAB-MS(Pos); 496(M⁺ + 1) 45 1 1-btria-O(CH₂)₃—NH—FAB-MS(Pos); 507(M⁺ + 1) 46 1 1-btria-O(CH₂)₂—NH— FAB-MS(Pos);493(M⁺ + 1) 47 1 (S)-H₂NOCCH(MeO₂C(CH₂)₂)—NH— FAB-MS(Pos); 475(M⁺ + 1)48 1 (S)-Ph-CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 494(M⁺ + 1) 49 1(R)-Ph-CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 494(M⁺ + 1) 50 1HOCH₂—CH(CO₂Me)-NH— FAB-MS(Pos); 434(M⁺ + 1) 51 1

FAB-MS(Pos); 658(M⁺ + 1) 52 2 (S)-H₂NOCCH(iBu)-NH— FAB-MS(Pos);445(M⁺ + 1) 53 2 HO(CH₂)₂—NH— FAB-MS(Pos); 376(M⁺ + 1)

TABLE 17

Ex Syn R Data 54 2 EtO₂C(CH₂)₂—NH— FAB-MS(Pos); 432(M⁺ + 1) 55 2EtO₂C(CH₂)₃—NH— FAB-MS(Pos); 446(M⁺ + 1) 56 2

FAB-MS(Pos); 488(M⁺ + 1) 57 2 1-Me₂N-cHex-(CH₂)₂—NH— FAB-MS(Pos);485(M⁺ + 1) 58 2 4-EtO₂C-Ph-NH— FAB-MS(Pos); 480(M⁺ + 1) 59 2

FAB-MS(Pos); 502(M⁺ + 1) 60 2 (1R,2S)-2-Ph-cPr-NH— FAB-MS(Pos);448(M⁺ + 1) 61 2 (3R)-3-(2-bimid)-1-pipe FAB-MS(Pos); 516(M⁺ + 1) 62 2(3S)-3-(2-bimid)-1-pipe FAB-MS(Pos); 516(M⁺ + 1) 63 2(1R,2S)-2-(3,4-diF-Ph)-cPr-NH— FAB-MS(Pos); 484(M⁺ + 1) 64 2H₂NOCCH₂—NH— FAB-MS(Pos); 389(M⁺ + 1) 65 2 H₂NOC(CH₂)₂—NH— FAB-MS(Pos);403(M⁺ + 1) 66 2 3-EtO₂C-Ph-NH— FAB-MS(Pos); 480(M⁺ + 1) 67 22-EtO₂C-Ph-NH— FAB-MS(Pos); 480(M⁺ + 1) 68 2 3-H₂NOC-Ph-NH— FAB-MS(Pos);451(M⁺ + 1) 69 2

FAB-MS(Pos); 532(M⁺ + 1) 70 2 4-EtO₂C-1-pipe FAB-MS(Pos); 472(M⁺ + 1) 712 4-HO-Ph-NH— FAB-MS(Pos); 424(M⁺ + 1) 72 2 3-HO-Ph-NH— FAB-MS(Pos);424(M⁺ + 1) 73 2 2-HO-Ph-NH— FAB-MS(Pos); 424(M⁺ + 1) 74 24-H₂NOC-1-pipe FAB-MS(Pos); 443(M⁺ + 1) 75 2 HO₃S(CH₂)₂—NH— FAB-MS(Pos);440(M⁺ + 1) 76 2 HO₃SO(CH₂)₂—NH— FAB-MS(Pos); 456(M⁺ + 1) 77 22-HO-6-O₂N-Ph-NH— FAB-MS(Pos); 469(M⁺ + 1) 78 2 2-H₂N-6-HO-Ph-NH—FAB-MS(Pos); 439(M⁺ + 1)

TABLE 18

Ex Syn R Data 79 2 6-AcO-2-AcNH-Ph-NH— FAB-MS(Pos); 523(M⁺ + 1) 80 22-AcNH-3-HO-Ph-NH— FAB-MS(Pos); 481(M⁺ + 1) 81 2 2-AcNH-6-HO-Ph-NH—FAB-MS(Pos); 481(M⁺ + 1) 82 2 2-BzNH-6-HO-Ph-NH— FAB-MS(Pos);543(M⁺ + 1) 83 2 2-BzNH-3-HO-Ph-NH— FAB-MS(Pos); 543(M⁺ + 1) 84 26-HO-2-(Ph-HNOC)-Ph-NH— FAB-MS(Pos); 543(M⁺ + 1) 85 26-HO-2-(Me-HNOC)-Ph-NH— FAB-MS(Pos); 481(M⁺ + 1) 86 21,3,4-thiadiazol-2-yl-NH— ESI-MS(Pos); 416(M⁺ + 1) 87 2 2-MeO-Ph-NH—ESI-MS(Pos); 438(M⁺ + 1) 88 2 3,4-diMeO-Ph-NH— ESI-MS(Pos); 468(M⁺ + 1)89 2 3-HO-2-Me-Ph-NH— ESI-MS(Pos); 438(M⁺ + 1) 90 2 4-HO-2-Me-Ph-NH—ESI-MS(Pos); 438(M⁺ + 1) 91 2 4-HO-3-O₂N-Ph-NH— ESI-MS(Pos); 469(M⁺ + 1)92 2 3-Et₂NCH₂-4-HO-Ph-NH— ESI-MS(Pos); 509(M⁺ + 1) 93 2 3-HO-2-Py-NH—ESI-MS(Pos); 425(M⁺ + 1) 94 2 2-HOCH₂-Ph-NH— ESI-MS(Pos); 438(M⁺ + 1) 952 3-HOCH₂-Ph-NH— ESI-MS(Pos); 438(M⁺ + 1) 96 2 4-HOCH₂-Ph-NH—ESI-MS(Pos); 438(M⁺ + 1) 97 2 2-HO(CH₂)₂Ph-NH— ESI-MS(Pos); 452(M⁺ + 1)98 2 indol-5-yl-NH— ESI-MS(Pos); 447(M⁺ + 1) 99 2 indazol-5-yl-NH—ESI-MS(Pos); 448(M⁺ + 1) 100 2 4-AcNH-Ph-NH— ESI-MS(Pos); 465(M⁺ + 1)101 2 4-(4-mor-CO)-Ph-NH— ESI-MS(Pos); 521(M⁺ + 1) 102 2 3-Ac-Ph-NH—ESI-MS(Pos); 450(M⁺ + 1) 103 2 Bn-NH— ESI-MS(Pos); 422(M⁺ + 1) 104 22-Me-Bn-NH— ESI-MS(Pos); 436(M⁺ + 1) 105 2 2-F-Bn-NH— ESI-MS(Pos);440(M⁺ + 1) 106 2 3-F-Bn-NH— ESI-MS(Pos); 440(M⁺ + 1) 107 2 4-F-Bn-NH—ESI-MS(Pos); 440(M⁺ + 1) 108 2 3-MeO-Bn-NH— ESI-MS(Pos); 452(M⁺ + 1) 1092 4-MeO-Bn-NH— ESI-MS(Pos); 452(M⁺ + 1) 110 2 2,4-diMeO-Bn-NH—ESI-MS(Pos); 482(M⁺ + 1) 111 2 3,5-diMeO-Bn-NH— ESI-MS(Pos); 482(M⁺ + 1)112 2 3-O₂N-Bn-NH— ESI-MS(Pos); 467(M⁺ + 1) 113 2 4-O₂N-Bn-NH—ESI-MS(Pos); 467(M⁺ + 1) 114 2 Ph₂CH—NH— ESI-MS(Pos); 498(M⁺ + 1)

TABLE 19

Ex Syn R Data 115 2 2-fur-CH₂—NH— ESI-MS(Pos); 412 (M⁺ + 1) 116 22-the-CH₂—N— ESI-MS(Pos); 428 (M⁺ + 1) 117 2 3-Py-CH₂—N— ESI-MS(Pos);423 (M⁺ + 1) 118 2 4-Py-CH₂—N— ESI-MS(Pos); 423 (M⁺ + 1) 119 22-F-Ph-(CH₂)₂—NH— ESI-MS(Pos); 454 (M⁺ + 1) 120 2 3-F-Ph-(CH₂)₂—NH—ESI-MS(Pos); 454 (M⁺ + 1) 121 2 4-F-Ph-(CH₂)₂—NH— ESI-MS(Pos); 454(M⁺ + 1) 122 2 4-Me-Ph-(CH₂)₂—NH— ESI-MS(Pos); 450 (M⁺ + 1) 123 24-MeO-Ph-(CH₂)₂—NH— ESI-MS(Pos); 466 (M⁺ + 1) 124 2 2-Cl-Ph-(CH₂)₂—NH—ESI-MS(Pos); 470 (M⁺ + 1) 125 2 4-Cl-Ph-(CH₂)₂—NH— ESI-MS(Pos); 470(M⁺ + 1) 126 2 4-Br-Ph-(CH₂)₂—NH— ESI-MS(Pos); 514, 516 (M⁺ + 1) 127 22-the-(CH₂)₂—NH— ESI-MS(Pos); 442 (M⁺ + 1) 128 2 2-Py-(CH₂)₂—NH—ESI-MS(Pos); 437 (M⁺ + 1) 129 2 3-Py-(CH₂)₂—NH— ESI-MS(Pos); 437(M⁺ + 1) 130 2 4-Py-(CH₂)₂—NH— ESI-MS(Pos); 437 (M⁺ + 1) 131 22,5-diMeO-Ph-(CH₂)₂—NH— ESI-MS(Pos); 496 (M⁺ + 1) 132 23,4-diMeO-Ph-(CH₂)₂—NH— ESI-MS(Pos); 496 (M⁺ + 1) 133 2indol-3-yl-(CH₂)₂—NH— ESI-MS(Pos); 475 (M⁺ + 1) 134 2 Me₂NCH(Ph)CH₂—N—ESI-MS(Pos); 479 (M⁺ + 1) 135 2 PhS(═O)₂—(CH₂)₂—NH— ESI-MS(Pos); 500(M⁺ + 1) 136 2 (3-Me-Ph)-N(Et)-(CH₂)₂—NH— ESI-MS(Pos); 493 (M⁺ + 1) 1372 4-Ph-1-pipa-CH₂CH(Me)-NH— ESI-MS(Pos); 534 (M⁺ + 1) 138 2PhO-CH₂CH(4-mor-CH₂)—NH— ESI-MS(Pos); 551 (M⁺ + 1) 139 24-(4-F-Bn)-2-mor-CH₂—N— ESI-MS(Pos); 539 (M⁺ + 1) 140 2 Et-NH—ESI-MS(Pos); 360 (M⁺ + 1) 141 2 nPen-NH— ESI-MS(Pos); 402 (M⁺ + 1) 142 2HOCH₂CH(Me)-NH— ESI-MS(Pos); 390 (M⁺ + 1) 143 2 HOCH(Me)CH₂—N—ESI-MS(Pos); 390 (M⁺ + 1) 144 2 HO(CH₂)₂O(CH₂)₂—NH— ESI-MS(Pos); 420(M⁺ + 1) 145 2 (HOCH₂)₂CH—NH— ESI-MS(Pos); 406 (M⁺ + 1) 146 2HOCH₂CH(HO)CH₂—N— ESI-MS(Pos); 406 (M⁺ + 1) 147 2 HO(CH₂)₅—NH—ESI-MS(Pos); 418 (M⁺ + 1) 148 2 cPen-NH— ESI-MS(Pos); 400 (M⁺ + 1) 149 2(1S,2S)-2-MeS-cPen-NH— ESI-MS(Pos); 446 (M⁺ + 1)

TABLE 20

Ex Syn R Data 150 2 (3S,4R)-4-MeS-3-THF-NH— ESI-MS(Pos); 448(M⁺ + 1) 1512 3-Bn-1-pyrr ESI-MS(Pos); 476(M⁺ + 1) 152 2 3-PhS(═O)2-1-pyrrESI-MS(Pos); 526(M⁺ + 1) 153 2 4-(2-oxo-1-bimid)-1-pipe ESI-MS(Pos);532(M⁺ + 1) 154 2 4-(2-Cl-Ph)-1-pipa ESI-MS(Pos); 511(M⁺ + 1) 155 24-(3-F₃C-Ph)-1-pipa ESI-MS(Pos); 545(M⁺ + 1) 156 2 4-(2-Py)-1-pipaESI-MS(Pos); 478(M⁺ + 1) 157 2 (1R,2R)2-Me₂N-cHex-N(allyl)- ESI-MS(Pos);497(M⁺ + 1) 158 4 (1RS,2SR,3RS,4SR)-2,3,4-triHO-cHex-NH— FAB-MS(Pos);462(M⁺ + 1) 159 4 (1RS,2SR,3SR,4SR)- FAB-MS(Pos); 492(M⁺ + 1)(2,3-diHO-4-HO(CH₂)₂O)-cPen-NH— 160 5 HO₂C(CH₂)₂—CH(CONMe₂)—FAB-MS(Pos); 489(M⁺ + 1) 161 6 HO₂CCH₂—N— FAB-MS(Pos); 390(M⁺ + 1) 162 6HO₂C(CH₂)₂—NH— FAB-MS(Pos); 404(M⁺ + 1) 163 6 HO₂C(CH₂)₃—NH—FAB-MS(Pos); 418(M⁺ + 1) 164 6 4-HO₂C-Ph-NH— FAB-MS(Pos); 452(M⁺ + 1)165 6 HO₂C(CH₂)₄—NH— FAB-MS(Pos); 432(M⁺ + 1) 166 6 HO₂C(CH₂)₃-N(Me)-FAB-MS(Pos); 432(M⁺ + 1) 167 6 4-HO₂C-1-pipe FAB-MS(Pos); 444(M⁺ + 1)168 6 3-HO₂C-Ph-NH— FAB-MS(Pos); 452(M⁺ + 1) 169 6 2-HO₂C-Ph-NH—FAB-MS(Pos); 452(M⁺ + 1) 170 6 2-HO₂C-1-pyrr FAB-MS(Pos); 430(M⁺ + 1)171 6 (S)-Ph-CH₂CH(CO₂H)—NH— FAB-MS(Pos); 480(M⁺ + 1) 172 6(R)-Ph-CH₂CH(CO₂H)—NH— FAB-MS(Pos); 480(M⁺ + 1) 173 6 HOCH₂—CH(CO₂H)—NH—FAB-MS(Pos); 420(M⁺ + 1) 174 8 H₂NNH— FAB-MS(Pos); 347(M⁺ + 1), Sal HCl175 9 H₂NOC(CH₂)₄—NH— FAB-MS(Pos); 431(M⁺ + 1) 176 9 H₂NOC(CH₂)₃—N(Me)-FAB-MS(Pos); 431(M⁺ + 1) 177 9 4-H₂NOC-Ph-NH— FAB-MS(Pos); 451(M⁺ + 1)

TABLE 21

Ex Syn R Data 178 2 (HO)₂(O)P-O(CH₂)₂NH— FAB-MS(Neg); 454(M⁺ − 1) 179 2(3-(MeO₂CCH₂)-Ph)-NH— FAB-MS(Pos); 480(M⁺ + 1) 180 2(4-(EtO₂CCH₂)-Ph)-NH— FAB-MS(Pos); 494(M⁺ + 1) 181 6(3-(HO₂CCH₂)-Ph)-NH— FAB-MS(Pos); 466(M⁺ + 1) 182 6(4-(HO₂CCH₂)-Ph))-NH— FAB-MS(Pos); 466(M⁺ + 1) 183 1 3-EtO₂C-2-thiqFAB-MS(Pos); 520(M⁺ + 1) 184 6 3-HO₂C-2-thiq FAB-MS(Pos); 492(M⁺ + 1)185 2 (HO)₂(O)P-(CH₂)₃NH— FAB-MS(Pos); 454(M⁺ + 1) 186 2(S)-tBuO₂C(CH₂)₂CH(CONH₂)NH— FAB-MS(Pos); 517(M⁺ + 1) 187 5(S)-HO₂C(CH₂)₂CH(CONH₂)NH— FAB-MS(Pos); 461(M⁺ + 1) 188 2(EtO)₂(O)P—CH₂NH— FAB-MS(Pos); 482(M⁺ + 1) 189 7 (HO)₂(O)P—CH₂NH—ESI-MS(Pos); 426(M⁺ + 1)

TABLE 22

Ex Syn R Data 1 1 cPen FAB-MS(Pos); 458(M⁺ + 1) 11 11 HOCH₂CH(OH)CH₂—FAB-MS(Pos); 464(M⁺ + 1) 14 14 1-Me-3-pyrr FAB-MS(Pos); 473(M⁺ + 1) 1616 CF₃CH₂— FAB-MS(Pos); 472(M⁺ + 1) 17 17 Boc-NH(CH₂)₂— FAB-MS(Pos);533(M⁺ + 1) 19 19 1-pipe-(CH₂)₂— FAB-MS(Pos.); 501(M⁺ + 1) 20 201-Ac-3-pyrr FAB-MS(Pos); 501(M⁺ + 1) 21 21 H FAB-MS(Pos.); 390(M⁺ + 1)25 25 1-Bn-3-pyrr FAB-MS(Pos); 549(M⁺ + 1) 26 26(1RS,2SR,3RS,4SR)-2,3,4- FAB-MS(Pos); 506(M⁺ + 1) triHO-cPen 29 291-MeSO₂-3-pyrr FAB-MS(Pos); 537(M⁺ + 1) 31 31 3-pyrr FAB-MS(Pos);459(M⁺ + 1) 190 1 Me FAB-MS(Pos); 404(M⁺ + 1) 191 1 iPr FAB-MS(Pos);432(M⁺ + 1) 192 1 Bn FAB-MS(Pos); 480(M⁺ + 1) 193 1 4-OMe-BnFAB-MS(Pos); 510(M⁺ + 1) 194 1 Ph FAB-MS(Pos); 466(M⁺ + 1) 195 1 cHexFAB-MS(Pos); 472(M⁺ + 1) 196 1 allyl FAB-MS(Pos); 430(M⁺ + 1) 197 1(1,3-dioxolan-2-yl)-CH₂— FAB-MS(Pos); 476(M⁺ + 1) 198 1 2-THP—O—(CH₂)₂—FAB-MS(Pos); 518(M⁺ + 1) 199 1 (R)-3-THF FAB-MS(Pos); 460(M⁺ + 1) 200 4HO—(CH₂)₂— FAB-MS(Pos); 434(M⁺ + 1) 201 1 (S)-3-THF FAB-MS(Pos);460(M⁺ + 1) 202 1 cPr FAB-MS(Pos); 430(M⁺ + 1) 203 1 cBu FAB-MS(Pos);444(M⁺ + 1) 204 1 tBu FAB-MS(Pos); 446(M⁺ + 1) 205 1 3-THF FAB-MS(Pos);46O(M⁺ + 1) 206 1 MeO—(CH₂)₂— FAB-MS(Pos); 448(M⁺ + 1) 207 11-Boc-3-pyrr FAB-MS(Pos); 559(M⁺ + 1) 208 1 sBu FAB-MS(Pos); 446(M⁺ + 1)209 1 (Et)₂CH— FAB-MS(Pos); 460(M⁺ + 1) 210 8 3-pyrr FAB-MS(Pos);459(M⁺ + 1), Sal HCl 211 1 iPrCH(Me)- FAB-MS(Pos); 460(M⁺ + 1) 212 1iBuCH(Me)- FAB-MS(Pos); 474(M⁺ + 1) 213 1 tBuCH(Me)- FAB-MS(Pos);474(M⁺ + 1) 214 1 iBu FAB-MS(Pos); 446(M⁺ + 1) 215 1 oxetan-3-ylFAB-MS(Pos); 446(M⁺ + 1) 216 1 4-THP FAB-MS(Pos); 474(M⁺ + 1) 217 11-Boc-4-pipe FAB-MS(Pos); 573(M⁺ + 1)

TABLE 23

Ex Syn R Data 218 8 4-pipe FAB-MS(Pos); 473(M⁺ + 1), Sal: HCl 219 141-Me-4-pipe FAB-MS(Pos); 487(M⁺ + 1) 220 16

FAB-MS(Pos); 546(M⁺ + 1) 221 1 1-Me-azetidin-3-yl FAB-MS(Pos);459(M⁺ + 1) Sal: HCl 222 16

FAB-MS(Pos); 484(M⁺ + 1) 223 16 nPrCH(Me)- FAB-MS(Pos); 460(M⁺ + 1) 22416 (nPr)₂CH— FAB-MS(Pos); 488(M⁺ + 1) 225 16 nPrCH(Et)- FAB-MS(Pos);474(M⁺ + 1) 226 16

FAB-MS(Pos); 484(M⁺ + 1) 227 16 CF₃CH(Me)- ESI-MS(Pos); 486(M⁺ + 1) 22816 cyclopent-3-en-1-yl FAB-MS(Pos); 456(M⁺ + 1) 229 1 MeHNOC-CH₂—FAB-MS(Pos.); 461(M⁺ + 1) 230 1 (4-Me-1-pipa)-CO—CH₂— FAB-MS(Pos.);530(M⁺ + 1) 231 1 (4-mor)-CO—CH₂— FAB-MS(Pos.); 517(M⁺ + 1) 232 191-pyrr-(CH₂)₂— FAB-MS(Pos.); 487(M⁺ + 1) 233 14 Me₂N(CH₂)₂—FAB-MS(Pos.); 461(M⁺ + 1) 234 20 AcNH(CH₂)₂— FAB-MS(Pos.); 475(M⁺ + 1)235 29 MeSO₂NH(CH₂)₂— FAB-MS(Pos.); 511(M⁺ + 1) 236 12,2-diMe-1,3-dioxan-5-yl FAB-MS(Pos.); 504(M⁺ + 1) 237 22 (HOCH₂)₂CH—FAB-MS(Pos.); 464(M⁺ + 1) 238 1 (MeOCH₂)₂CH— FAB-MS(Pos.); 492(M⁺ + 1)239 1 (AcNHCH₂)₂CH— FAB-MS(Pos.); 546(M⁺ + 1) 240 16 AcNH(CH₂)₃—ESI-MS(Pos); 489(M⁺ + 1) 241 16 (FCH₂)₂CH— FAB-MS(Pos); 468(M⁺ + 1) 24216 FCH₂CH(Me)- FAB-MS(Pos); 450(M⁺ + 1) 243 16 isopropenyl FAB-MS(Pos);430(M⁺ + 1) 244 16 H₂C═C(CH₂F)— FAB-MS(Pos); 448(M⁺ + 1) 245 16MeOCH₂CH(Me)- FAB-MS(Pos); 462(M⁺ + 1) 246 16 4,4-dimethyl-cHexFAB-MS(Pos); 500(M⁺ + 1) 247 16 AcNHCH₂CH(Me)- FAB-MS(Pos); 489(M⁺ + 1)248 16 AcN(Me)(CH₂)₂— FAB-MS(Pos); 489(M⁺ + 1) 249 16 AcN(Me)CH₂CH(Me)-FAB-MS(Pos); 503(M⁺ + 1) 250 1 3-methylcyclopent-3-en-1yl FAB-MS(Pos);470(M⁺ + 1) 251 16 2-THP-OCH₂CH(Me)- ESI-MS(Pos); 532(M⁺ + 1) 252 4HOCH₂CH(Me)- FAB-MS(Pos); 448(M⁺ + 1) 253 16 2,2-diethyl-1,3-dioxan-5-ylFAB-MS(Pos); 532(M⁺ + 1)

TABLE 24

Ex Syn R Data 6 6 cPen FAB-MS(Pos); 430(M⁺ + 1) 30 30 H₂N(CH₂)₂—FAB-MS(Pos); 405(M⁺ + 1) 32 32 (FCH₂)₂CH— FAB-MS(Pos); 440(M⁺ + 1) 254 6Me FAB-MS(Pos); 376(M⁺ + 1) 255 6 iPr FAB-MS(Pos); 404(M⁺ + 1) 256 6 BnFAB-MS(Pos); 452(M⁺ + 1) 257 6 4-MeO-Bn FAB-MS(Pos); 482(M⁺ + 1) 258 6Ph FAB-MS(Pos); 438(M⁺ + 1) 259 6 cHex FAB-MS(Pos); 444(M⁺ + 1) 260 6Allyl FAB-MS(Pos); 402(M⁺ + 1) 261 6 HOCH₂CH(OH)CH₂— FAB-MS(Pos);436(M⁺ + 1) 262 6 (1,3-dioxolan-2-yl)-CH₂— FAB-MS(Pos); 448(M⁺ + 1) 2636 2-THP-O-(CH₂)₂— FAB-MS(Pos); 49O(M⁺ + 1) 264 6 (R)-3-THF FAB-MS(Pos);432(M⁺ + 1) 265 6 HO-(CH₂)₂— FAB-MS(Pos); 406(M⁺ + 1) 266 6 (S)-3-THFFAB-MS(Pos); 432(M⁺ + 1) 267 6 cPr FAB-MS(Pos); 402(M⁺ + 1) 268 6 cBuFAB-MS(Pos); 416(M⁺ + 1) 269 6 tBu FAB-MS(Pos); 418(M⁺ + 1) 270 6 3-THFFAB-MS(Pos); 432(M⁺ + 1) 271 6 MeO(CH₂)₂— FAB-MS(Pos); 420(M⁺ + 1) 272 61-Boc-3-pyrr FAB-MS(Pos); 531(M⁺ + 1) 273 6 sBu FAB-MS(Pos); 418(M⁺ + 1)274 6 (Et)₂CH— FAB-MS(Pos); 432(M⁺ + 1) 275 8 3-pyrr ESI-MS(Pos);431(M⁺ + 1), Sal: HCl 276 6 iPrCH(Me)- FAB-MS(Pos); 432(M⁺ + 1) 277 6iBuCH(Me)- FAB-MS(Pos); 446(M⁺ + 1) 278 6 tBuCH(Me)- FAB-MS(Pos);446(M⁺ + 1) 279 6 1-Me-3-pyrr ESI-MS(Pos); 445(M⁺ + 1), Sal: HCl 280 6iBu FAB-MS(Pos); 418(M⁺ + 1) 281 6 oxetan-3-yl FAB-MS(Pos); 418(M⁺ + 1)282 6 4-THP FAB-MS(Pos); 446(M⁺ + 1) 283 6 1-Ac-3-pyrr FAB-MS(Pos);473(M⁺ + 1) 284 6 1-MeSO₂-3-pyrr FAB-MS(Pos); 509(M⁺ + 1) 285 61-Bn-3-pyrr FAB-MS(Pos); 521(M⁺ + 1) 286 6 1-Me-4-pipe FAB-MS(Pos);459(M⁺ + 1)

TABLE 25

Ex Syn R Data 287 6

FAB-MS(Pos); 518(M⁺ + 1) 288 6 (1RS,2SR,3R5,4SR)-2,3,4-triHO-cPenFAB-MS(Pos); 478(M⁺ + 1) 289 6 1-Me-azetidin-3-yl FAB-MS(Pos);431(M⁺ + 1) 290 6

FAB-MS(Pos); 456(M⁺ + 1) 291 6 nPrCH(Me)- FAB-MS(Pos); 432(M⁺ + 1) 292 6(nPr)₂CH— FAB-MS(Pos); 460(M⁺ + 1) 293 6 nPrCH(Et)- FAB-MS(Pos);446(M⁺ + 1) 294 6 CF₃CH₂— FAB-MS(Pos); 444(M⁺ + 1) 295 6

FAB-MS(Pos); 456(M⁺ + 1) 296 6 CF₃CH(Me)- FAB-MS(Pos); 458(M⁺ + 1) 297 6cyclopent-3-en-1-yl FAB-MS(Pos); 428(M⁺ + 1) 298 6 1-pipe-(CH₂)₂—ESI-MS(Pos.); 473(M⁺ + 1) 299 6 MeHNOC—CH₂— FAB-MS(Pos.); 433(M⁺ + 1)300 6 (4-Me-1-pipa)-CO—CH₂— FAB-MS(Pos.); 502(M⁺ + 1) 301 6(4-mor)-(CH₂)₂— FAB-MS(Pos.); 475(M⁺ + 1) 302 6 1-pyrr-(CH₂)₂—ESI-MS(Pos.); 459(M⁺ + 1) 303 6 Me₂N(CH₂)₂— FAB-MS(Pos.); 433(M⁺ + 1)304 6 AcNH(CH₂)₂— FAB-MS(Pos.); 447(M⁺ + 1) 305 6 MeSO₂NH(CH₂)₂—FAB-MS(Pos.); 483(M⁺ + 1) 306 6 2,2-diMe-1,3-dioxan-5-yl FAB-MS(Pos.);476(M⁺ + 1) 307 22 (HOCH₂)₂CH— FAB-MS(Pos.); 436(M⁺ + 1) 308 6 HFAB-MS(Pos.); 362(M⁺ + 1) 309 6 (MeOCH₂)₂CH— FAB-MS(Pos.); 464(M⁺ + 1)310 6 (AcNHCH₂)₂CH— FAB-MS(Pos.); 518(M⁺ + 1) 311 6 AcNH(CH₂)₃—FAB-MS(Pos); 461(M⁺ + 1) 312 6 FCH₂CH(Me)- FAB-MS(Pos); 422(M⁺ + 1) 3136 isopropenyl FAB-MS(Pos); 402(M⁺ + 1) 314 6 H₂C═C(CH₂F)— FAB-MS(Pos);420(M⁺ + 1) 315 6 MeOCH₂CH(Me)- FAB-MS(Pos); 434(M⁺ + 1) 316 64,4-dimethyl-cHex FAB-MS(Pos); 472(M⁺ + 1) 317 6 AcNHCH₂CH(Me)-ESI-MS(Pos); 461(M⁺ + 1) 318 6 AcN(Me)(CH₂)₂— FAB-MS(Pos); 461(M⁺ + 1)319 6 AcN(Me)CH₂CH(Me)- FAB-MS(Pos); 475(M⁺ + 1) 320 63-methylcyclopent-3-en-1yl FAB-MS(Pos); 442(M⁺ + 1) 321 6 HOCH₂CH(Me)-FAB-MS(Pos); 420(M⁺ + 1) 322 6 2,2-diethyl-1,3-dioxan-5-yl FAB-MS(Pos);504(M⁺ + 1)

TABLE 26

Ex Syn R¹ R² R³ R⁴ Data 34 34 NHAc F H CO₂Et FAB-MS(Pos); 475(M⁺ + 1)323 1 H H H CO₂Et FAB-MS(Pos); 400(M⁺ + 1) 324 1 H Br H CO₂EtFAB-MS(Pos); 478, 480(M⁺ + 1) 325 6 H H H CO₂H FAB-MS(Pos); 372(M⁺ + 1)326 6 H Br H CO₂H FAB-MS(Pos); 450, 452(M⁺ + 1) 327 1 H Me H CO₂EtFAB-MS(Pos); 414(M⁺ + 1) 328 6 H Me H CO₂H FAB-MS(Pos); 386(M⁺ + 1) 3291 H F Cl CO₂Et FAB-MS(Pos); 452(M⁺ + 1) 330 6 H F Cl CO₂H FAB-MS(Pos);424(M⁺ + 1) 331 1 H Cl H CO₂Et FAB-MS(Pos); 434(M⁺ + 1) 332 6 H Cl HCO₂H FAB-MS(Pos); 406(M⁺ + 1) 333 1 H F F CO₂Et FAB-MS(Pos); 436(M⁺ + 1)334 6 H F F CO₂H FAB-MS(Pos); 408(M⁺ + 1) 335 16 F F H CO₂EtFAB-MS(Pos); 436(M⁺ + 1) 336 6 F F H CO₂H FAB-MS(Pos); 408(M⁺ + 1) 33716 OMe F H CO₂Et ESI-MS(Pos); 448(M⁺ + 1) 338 6 OMe F H CO₂HFAB-MS(Pos); 420(M⁺ + 1) 339 16 NH₂ F H CO₂Et ESI-MS(Pos); 433(M⁺ + 1)340 6 NH₂ F H CO₂H FAB-MS(Pos); 405(M⁺ + 1) 341 16 NHMe F H CO₂EtFAB-MS(Pos); 447(M⁺ + 1) 342 6 NHMe F H CO₂H FAB-MS(Pos); 419(M⁺ + 1)343 16 NH(cHex) F H CO₂Et FAB-MS(Pos); 515(M⁺ + 1) 344 6 NH(cHex) F HCO₂H FAB-MS(Pos); 487(M⁺ + 1) 345 6 NHAc F H CO₂H FAB-MS(Pos);447(M⁺ + 1) 346 16 N(Me)Ac F H CO₂Et FAB-MS(Pos); 531(M⁺ + 1) 347 6N(Me)Ac F H CO₂H FAB-MS(Pos); 503(M⁺ + 1)

TABLE 27

Ex Syn R¹ R² R³ R⁴ Data 33 33 NMe₂ F H CO₂Et FAB-MS(Pos); 503(M⁺ + 1)348 16 F F H CO₂Et FAB-MS(Pos); 478(M⁺ + 1) 349 6 F F H CO₂HFAB-MS(Pos); 450(M⁺ + 1) 350 6 NMe₂ F H CO₂H FAB-MS(Pos); 475(M⁺ + 1)351 33 1-pyrr F H CO₂Et FAB-MS(Pos); 529(M⁺ + 1) 352 6 1-pyrr F H CO₂HFAB-MS(Pos); 501(M⁺ + 1) 353 16 OBn F H CO₂Et ESI-MS(Pos); 566(M⁺ + 1)354 18 OH F H CO₂Et FAB-MS(Pos); 476(M⁺ + 1) 355 6 OH F H CO₂HFAB-MS(Pos); 448(M⁺ + 1)

TABLE 28

Ex Syn R¹ R² Data 8 8 4-pipe CO₂H FAB-MS(Pos); 391(M⁺ + 1), Sal: HCl 1313 cHexCH₂— CO₂H FAB-MS(Pos); 404(M⁺ + 1) 356 1 iPr CO₂Et FAB-MS(Pos);378(M⁺ + 1) 357 1 tBu CO₂Et FAB-MS(Pos); 392(M⁺ + 1) 358 1 4-THP CO₂EtFAB-MS(Pos); 420(M⁺ + 1) 359 1 cPen CO₂Et FAB-MS(Pos); 404(M⁺ + 1) 360 11-Boc-4-pipe CO₂Et FAB-MS(Pos); 519(M⁺ + 1) 361 1 Ph CO₂Et FAB-MS(Pos);412(M⁺ + 1) 362 1 cHep CO₂Et FAB-MS(Pos); 432(M⁺ + 1) 363 1 cOct CO₂EtFAB-MS(Pos); 446(M⁺ + 1) 364 1 1-Me-cHex CO₂Et FAB-MS(Pos); 432(M⁺ + 1)365 1 4-THSP CO₂Et FAB-MS(Pos); 436(M⁺ + 1) 366 14 1-Me-4-pipe CO₂EtFAB-MS(Pos); 433(M⁺ + 1) 367 1 4-Me-cHex CO₂Et FAB-MS(Pos); 432(M⁺ + 1)368 1 4-Me-cHex CO₂Et FAB-MS(Pos); 432(M⁺ + 1) 369 1 4,4-diF-cHex CO₂EtFAB-MS(Pos); 454(M⁺ + 1) 370 6 iPr CO₂H FAB-MS(Pos); 350(M⁺ + 1) 371 6tBu CO₂H FAB-MS(Pos); 364(M⁺ + 1) 372 6 4-THP CO₂H FAB-MS(Pos);392(M⁺ + 1) 373 6 cPen CO₂H FAB-MS(Pos); 376(M⁺ + 1) 374 6 1-Boc-4-pipeCO₂H FAB-MS(Pos); 491(M⁺ + 1)

TABLE 29

Ex Syn R¹ R² Data 375 6 Ph CO₂H FAB-MS(Pos); 384(M⁺ + 1) 376 6 cHep CO₂HFAB-MS(Pos); 404(M⁺ + 1) 377 6 cOct CO₂H FAB-MS(Pos); 418(M⁺ + 1) 378 61-Me-cHex CO₂H FAB-MS(Pos); 404(M⁺ + 1) 379 6 4-THSP CO₂H FAB-MS(Pos);408(M⁺ + 1) 380 6 1-Me-4-pipe CO₂H FAB-MS(Pos); 405(M⁺ + 1) 381 64-Me-cHex CO₂H FAB-MS(Pos); 404(M⁺ + 1) 382 6 4-Me-cHex CO₂HFAB-MS(Pos); 404(M⁺ + 1) 383 6 4,4-diF-cHex CO₂H FAB-MS(Pos); 426(M⁺ +1)

TABLE 30

Ex Syn R1 R2 Data 384 1 4-THSP CO₂Et FAB-MS(Pos); 476(M⁺ + 1) 385 64-THSP CO₂H FAB-MS(Pos); 448(M⁺ + 1) 386 1 4,4-diF-cHex CO₂EtFAB-MS(Pos); 494(M⁺ + 1) 387 6 4,4-diF-cHex CO₂H FAB-MS(Pos);466(M⁺ + 1) 388 1 3-THP CO₂Et FAB-MS(Pos); 460(M⁺ + 1) 389 6 3-THP CO₂HFAB-MS(Pos); 432(M⁺ + 1)

TABLE 31

Ex Syn R Data 15 15 (HO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos); 480(M⁺ + 1), Sal:HBr 27 27 (tBuCO₂CH₂O)₂(O)P—(CH₂)₂NH— FAB-MS(Pos); 708(M⁺ + 1) 390 16(HO—CH₂CH₂)₂N— FAB-MS(Pos); 460(M⁺ + 1) 391 16 3-HO-1-pipe FAB-MS(Pos);456(M⁺ + 1) 392 16 HO—(CH₂)₃NH— FAB-MS(Pos); 430(M⁺ + 1) 393 163-(HO—CH₂)-1-pipe FAB-MS(Pos); 470(M⁺ + 1) 394 16 2-(HOCH₂)-1-pipeFAB-MS(Pos); 470(M⁺ + 1) 395 16 HO—CH₂CHOHCH₂NMe- FAB-MS(Pos);460(M⁺ + 1) 396 16 3-HO-1-pyrr FAB-MS(Pos); 442(M⁺ + 1) 397 16(S)-3-EtO₂C-2-thiq FAB-MS(Pos); 560(M⁺ + 1) 398 16 (R)-3-EtO₂C-2-thiqFAB-MS(Pos); 560(M⁺ + 1) 399 6 (S)-3-HO₂C-2-thiq FAB-MS(Pos);532(M⁺ + 1) 400 6 (R)-3-HO₂C-2-thiq FAB-MS(Pos); 532(M⁺ + 1) 401 16EtO₂C-CH₂NMe- FAB-MS(Pos); 472(M⁺ + 1) 402 16 2-EtO₂C-1-pyrrFAB-MS(Pos); 498(M⁺ + 1) 403 6 HO₂C-CH₂NMe- FAB-MS(Pos); 444(M⁺ + 1) 4046 2-HO₂C-1-pyrr FAB-MS(Pos); 470(M⁺ + 1) 405 1 (S)-EtO₂C-CHOH(CH₂)₂NH—FAB-MS(Pos); 502(M⁺ + 1) 406 6 (S)-HO₂C-CHOH(CH₂)₂NH— FAB-MS(Pos);474(M⁺ + 1) 407 16 4-HO-1-pipe FAB-MS(Pos); 456(M⁺ + 1) 408 16HO-(CH₂)₂NMe- FAB-MS(Pos); 430(M⁺ + 1) 409 16 HO-(CH₂)₂NBn- FAB-MS(Pos);506(M⁺ + 1) 410 1 2-Py-(CH₂)₂NH— FAB-MS(Pos); 477(M⁺ + 1) 411 1

FAB-MS(Pos); 528(M⁺ + 1) 412 1 (EtO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos);536(M⁺ + 1) 413 4 (1RS,2SR,3RS,4SR)-2,3,4-triHO-cPen FAB-MS(Pos);488(M⁺ + 1) 414 1 (S)-tBuO₂C-CH₂CH(CO₂tBu)-NH— FAB-MS(Pos); 600(M⁺ + 1)415 1 3-EtO₂C-2-thiq FAB-MS(Pos); 560(M⁺ + 1) 416 1 (HO)₂(O)P—O(CH₂)₂NH—FAB-MS(Neg); 494(M⁺ − 1) 417 5 (S)-HO₂C-CH₂CH(CO₂H)—NH— FAB-MS(Pos);488(M⁺ + 1)

TABLE 32

Ex Syn R Data 418 1

FAB-MS(Pos); 572(M⁺ + 1) 419 6 3-HO₂C-2-thiq FAB-MS(Pos); 532(M⁺ + 1)420 4 (1RS,2SR,3SR,4SR)-2,3-diHO-4- FAB-MS(Pos); 532(M⁺ + 1)(HO(CH₂)₂O)-cPen 421 1 (2-HO-Ph)-NH— FAB-MS(Pos); 464(M⁺ + 1) 422 1(3-HO-Ph)-NH— FAB-MS(Pos); 464(M⁺ + 1) 423 1 (4-HO-Ph)-NH— FAB-MS(Pos);464(M⁺ + 1) 424 1 (S)-tBuO₂C-(CH₂)₂CH(CO₂tBu)-NH— FAB-MS(Pos);614(M⁺ + 1) 425 5 (S)-HO₂C—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 502(M⁺ + 1)426 1 (EtO)₂(O)P—CH(CH₂cHex)CH₂NH— FAB-MS(Pos); 632(M⁺ + 1) 427 15(HO)₂(O)P—CH(CH₂cHex)CH₂NH— FAB-MS(Pos); 576(M⁺ + 1) Sal: HBr 428 1(EtO)₂(O)P—CH(Bn)-CH₂NH— FAB-MS(Pos); 626(M⁺ + 1) 429 7(HO)₂(O)P-CH(Bn)-CH₂NH— FAB-MS(Pos); 570(M⁺ + 1) 430 16 EtO₂C—CH₂NBn-FAB-MS(Pos); 548(M⁺ + 1) 431 6 HO₂C—CH₂NBn- FAB-MS(Pos); 520(M⁺ + 1) 43216 EtO₂C—CH(Bn)NMe- FAB-MS(Pos); 562(M⁺ + 1) 433 6 HO₂C—CH(Bn)NMe-FAB-MS(Pos); 534(M⁺ + 1) 434 16 (BnO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos);660(M⁺ + 1) 435 24 (BnO)(HO)(O)P—(CH₂)₂NH— FAB-MS(Pos); 570(M⁺ + 1) 43616 EtO₂C—CH(CH₂OH)NH— FAB-MS(Pos); 488(M⁺ + 1) 437 6 HO₂C—CH(CH₂OH)NH—FAB-MS(Pos); 460(M⁺ + 1) 438 16 (S)-MeO₂C—CH₂CH(CO₂tBu)-NH— FAB-MS(Pos);558(M⁺ + 1) 439 16 (S)-MeO₂C—(CH₂)₂CH(CO₂tBu)-NH— FAB-MS(Pos);572(M⁺ + 1) 440 5 (S)-MeO₂C—CH₂CH(CO₂H)—NH— FAB-MS(Pos); 502(M⁺ + 1) 4415 (S)-MeO₂C—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 516(M⁺ + 1) 442 18(tBuCO₂CH₂O)(HO)(O)P—(CH₂)₂NH— FAB-MS(Pos); 594(M⁺ + 1) 443 27(tBuCO₂CH₂O)(BnO)(O)P—(CH₂)₂NH— FAB-MS(Pos); 684(M⁺ + 1) 444 16(S)-tBuO₂C—(CH₂)₂CH(CO₂Me)-NH— FAB-MS(Pos); 572(M⁺ + 1) 445 5(S)-HO₂C—(CH₂)₂CH(CO₂Me)-NH— FAB-MS(Pos); 516(M⁺ + 1) 446 16(S)-tBuO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 558(M⁺ + 1) 447 5(S)-HO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 502(M⁺ + 1) 448 1 4-EtO₂C-1-pipeFAB-MS(Pos); 512(M⁺ + 1) 449 6 4-HO₂C-1-pipe FAB-MS(Pos); 484(M⁺ + 1)450 1 2-thiq FAB-MS(Pos); 488(M⁺ + 1) 451 1 HO—(CH₂)₂NH— FAB-MS(Pos);416(M⁺ + 1)

TABLE 33

Ex Syn R Data 452 1 EtO₂C—(CH₂)₂NH— FAB-MS(Pos); 472(M⁺ + 1) 453 163-EtO₂C-1-pipe ESI-MS(Pos); 512(M⁺ + 1) 454 6 3-HO₂C-1-pipe FAB-MS(Pos);484(M⁺ + 1) 455 6 HO₂C—(CH₂)₂NH— FAB-MS(Pos); 444(M⁺ + 1) 456 162-EtO₂C-1-pipe FAB-MS(Pos); 512(M⁺ + 1) 457 16 BocNHNH— FAB-MS(Pos);487(M⁺ + 1) 458 16 H₂N— ESI-MS(Pos); 372(M⁺ + 1) 459 16 MeHN—FAB-MS(Pos); 386(M⁺ + 1) 460 16 Me₂N— FAB-MS(Pos); 400(M⁺ + 1) 461 163-H₂NOC-2-thiq FAB-ESI(Pos); 531(M⁺ + 1) 462 8 H₂N—NH— FAB-MS(Pos);387(M⁺ + 1) 463 6 2-HO₂C-1-pipe FAB-MS(Pos); 484(M⁺ + 1) 464 16EtO₂C—(CH₂)₃NH— FAB-MS(Pos); 486(M⁺ + 1) 465 16 Boc-NH(CH₂)₂NH—ESI-MS(Pos); 515(M⁺ + 1) 466 16 Me₂N—(CH₂)₂NH— FAB-MS(Pos); 443(M⁺ + 1)467 6 HO₂C—(CH₂)₃NH— FAB-MS(Pos); 458(M⁺ + 1) 468 16(S)-EtO₂C—(CH₂)₂CH(CO₂Et)-NH— FAB-MS(Pos); 558(M⁺ + 1) 469 8H₂N—(CH₂)₂NH— FAB-MS(Pos); 415(M⁺ + 1), Sal: HCl 470 16 3-MeO₂C-4-morFAB-MS(Pos); 500(M⁺ + 1) 471 16 3-(HO—CH₂)-2-thiq FAB-MS(Pos);518(M⁺ + 1) 472 16 (S)-2-EtO₂C-1-pipe FAB-MS(Pos); 512(M⁺ + 1) 473 63-HO₂C-4-mor FAB-MS(Pos); 486(M⁺ + 1) 474 6 (S)-2-HO₂C-1-pipeFAB-MS(Pos); 484(M⁺ + 1) 475 16 (R)-2-EtO₂C-1-pipe FAB-MS(Pos);512(M⁺ + 1) 476 6 (R)-2-HO₂C-1-pipe FAB-MS(Pos); 484(M⁺ + 1) 477 12-((EtO)₂(O)P—CH₂)-1-pipe FAB-MS(Pos); 590(M⁺ + 1) 478 72-((HO)₂(O)P—CH₂)-1-pipe FAB-MS(Pos.); 534(M⁺ + 1)

TABLE 34

Ex Syn R Data 23 16,23 (R)-MeO₂C—CH(CH₂-(3-Py))-NH— FAB-MS(Pos);537(M⁺ + 1), Sal: HCl 28 28 HO₂C—C(Me)₂-NH— FAB-MS(Pos); 460(M⁺ + 1) 47916 3-EtO₂C-2-thiq FAB-MS(Pos); 562(M⁺ + 1) 480 6 3-HO₂C-2-thiqFAB-MS(Pos); 534(M⁺ + 1) 481 16 (EtO)₂(O)P—(CH₂)₂—NH— FAB-MS(Pos);538(M⁺ + 1) 482 7 (HO)₂(O)P—(CH₂)₂—NH— FAB-MS(Pos); 482(M⁺ + 1) 483 16(S)-EtO₂C—(CH₂)₂CH(CO₂Et)-NH— FAB-MS(Pos); 560(M⁺ + 1) 484 16EtO₂C—CH(CH₂OH)—NH— FAB-MS(Pos); 490(M⁺ + 1) 485 6(S)-HO₂C—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 504(M⁺ + 1) 486 6(R)-HO₂C—CH(CH₂-(3-Py))-NH— FAB-MS(Pos); 523(M⁺ + 1) 487 16(S)-MeO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 518(M⁺ + 1) 488 16(R)-MeO₂C—CH(Bn)-NH— FAB-MS(Pos); 484(M⁺ + 1) 489 16(R)-MeO₂C—CH(iBu)-NH— FAB-MS(Pos); 502(M⁺ + 1) 490 16(R)-MeO₂C—CH(Me)-NH— FAB-MS(Pos); 460(M⁺ + 1) 491 6 HO₂C—CH(CH₂OH)—NH—FAB-MS(Pos); 462(M⁺ + 1) 492 6 (S)-HO₂C—CH₂CH(CO₂H)—NH— FAB-MS(Pos);490(M⁺ + 1) 493 6 (R)-HO₂C—CH(Bn)-NH— FAB-MS(Pos); 522(M⁺ + 1) 494 6(R)-HO₂C—CH₂CH(CO₂H)—NH— FAB-MS(Pos); 490(M⁺ + 1) 495 6(S)-HO₂C—CH(iBu)-NH— FAB-MS(Pos); 488(M⁺ + 1) 496 16(R)-HO₂C—CH(iPr)-NH— FAB-MS(Pos); 488(M⁺ + 1) 497 16(S)-MeO₂C—CH₂CH(CO₂tBu)-NH— FAB-MS(Pos); 560(M⁺ + 1) 498 16(R)-MeO₂C—(CH₂)₂CH(CO₂Me)-NH— FAB-MS(Pos); 532(M⁺ + 1) 499 16(S)-MeO₂C—(CH₂)₂CH(CO₂tBu)-NH— FAB-MS(Pos); 574(M⁺ + 1) 500 16(R)-EtO₂C—CH(tBu)-NH— FAB-MS(Pos); 516(M⁺ + 1) 501 15(HO)₂(O)P—CF₂—CH₂NH— ESI-MS(Pos); 518(M⁺ + 1) Sal: HBr 502 16(R)-MeO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 518(M⁺ + 1) 503 5(S)-MeO₂C—CH₂CH(CO₂H)—NH— FAB-MS(Pos); 504(M⁺ + 1) 504 5(S)-MeO₂C—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 518(M⁺ + 1) 505 16(S)-MeO₂C—CH(iBu)-NH— FAB-MS(Pos); 502(M⁺ + 1) 506 28(R)-HO₂C—CH(tBu)-NH— FAB-MS(Pos); 488(M⁺ + 1) 507 6 (R)-HO₂C—CH(iBu)-NH—FAB-MS(Pos); 488(M⁺ + 1) 508 16 (1-MeO₂C-cPen)-NH— FAB-MS(Pos);500(M⁺ + 1) 509 28 (1-HO₂C-cPen)-NH— FAB-MS(Pos); 486(M⁺ + 1) 510 6(R)-HO₂C—CH(Me)-NH— FAB-MS(Pos); 446(M⁺ + 1) 511 6 (R)-HO₂C-CH(iPr)-NH—FAB-MS(Pos); 474(M⁺ + 1) 512 16 (S)-tBuO₂C—(CH₂)₂CH(CO₂Me)-NH—FAB-MS(Pos); 574(M⁺ + 1) 513 5 (S)-HO₂C—(CH₂)₂CH(CO₂Me)-NH— FAB-MS(Pos);518(M⁺ + 1) 514 16 (S)-tBuO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 560(M⁺ + 1)

TABLE 35

Ex Syn R Data 515 5 (S)-HO₂C—CH₂CH(CO₂Me)-NH— FAB-MS(Pos); 504(M⁺ + 1)516 6 (R)-HO₂C—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 504(M⁺ + 1) 517 12-((EtO)₂(O)P—CH₂)-1-pipe FAB-MS(Pos); 592(M⁺ + 1) 518 72-((HO)₂(O)P—CH₂)-1-pipe FAB-MS(Pos.); 536(M⁺ + 1) 519 1(EtO)₂(O)P—CH₂NH— FAB-MS(Pos.); 524(M⁺ + 1) 520 1 (EtO)₂(O)P—(CH₂)₃NH—FAB-MS(Pos.); 552(M⁺ + 1) 521 15 (HO)₂(O)P—CH₂NH— ESI-MS(Pos.);468(M⁺ + 1) Sal: HBr 522 15 (HO)₂(O)P—(CH₂)₃NH— ESI-MS(Pos.);496(M⁺ + 1) Sal: HBr 523 16 (EtO)₂(O)P—CF₂—CH₂NH— FAB-MS(Pos);574(M⁺ + 1) 524 16 EtO₂C—(CH₂)₂NH— FAB-MS(Pos); 474(M⁺ + 1) 525 6HO₂C—(CH₂)₂NH— FAB-MS(Pos); 446(M⁺ + 1) 526 6 HO₂C—(CH₂)₃NH—FAB-MS(Pos); 460(M⁺ + 1) 527 7 (HO)₂(O)P—C(Me)₂-CH₂NH— FAB-MS(Pos);510(M⁺ + 1) 528 16 (EtO)₂(O)P—C(Me)₂—CH₂NH— FAB-MS(Pos); 566(M⁺ + 1) 52916 (S)—EtO₂C—(CH₂)₃CH(CO₂Et)-NH— FAB-MS(Pos); 574(M⁺ + 1) 530 6(S)—HO₂C—(CH₂)₃CH(CO₂H)—NH— FAB-MS(Pos); 518(M⁺ + 1) 531 16(EtO₂C—CH₂)₂N— FAB-MS(Pos); 546(M⁺ + 1) 532 6 (HO₂C—CH₂)₂N— FAB-MS(Pos);476(M⁺ + 1) 533 16 (2-oxo-3-THF)—NH— FAB-MS(Pos); 458(M⁺ + 1) 534 6HO—(CH₂)₂CH(CO₂H)—NH— FAB-MS(Pos); 476(M⁺ + 1) 535 16(2,2-diMe-1,3-dioxolan-4-yl)—CH₂NH— FAB-MS(Pos); 488(M⁺ + 1) 536 4HO—CH₂CH(OH)CH₂—NH— FAB-MS(Pos); 448(M⁺ + 1) 537 16 3-EtO₂C-cHex-NH—FAB-MS(Pos); 528(M⁺ + 1) 538 6 3-HO₂C-cHex-NH— FAB-MS(Pos); 500(M⁺ + 1)539 16 (EtO₂CCH₂)₂CHNH— FAB-MS(Pos); 560(M⁺ + 1) 540 6 (HO₂CCH₂)₂CHNH—FAB-MS(Pos); 504(M⁺ + 1) 541 16 HO₂C—(CH₂)₄—NH— FAB-MS(Pos); 474(M⁺ + 1)542 16 (S)—HO₂CCHOH(CH₂)₂NH— FAB-MS(Pos); 476(M⁺ + 1) 543 16EtO₂C—(CH₂)₃NH— FAB-MS(Pos); 488(M⁺ + 1) 544 16 MeO₂C—C(Me)₂-NH—FAB-MS(Pos); 474(M⁺ + 1) 545 16 (EtO)₂(O)P-3-pipe- FAB-MS(Pos);578(M⁺ + 1) 546 7 (HO)₂(O)P-3-pipe- FAB-MS(Pos); 522(M⁺ + 1)

TABLE 36

Ex Syn R¹ R² Data 18 18 2,2-diMe-1,3- (HO)2(O)P-(CH₂)₂NH— FAB-MS(Pos.);526(M⁺ + 1) dioxan-5-yl 22 22 (HO—CH₂)₂CH— (HO)2(O)P-(CH₂)₂NH—FAB-MS(Pos.); 486(M⁺ + 1) 547 16 (S)-3-THF HO—(CH₂)₃NH— FAB-MS(Pos);432(M⁺ + 1) 548 16 (R)-3-THF HO—(CH₂)₃NH— FAB-MS(Pos); 432(M⁺ + 1) 54916 1-Me-4-pipe HO—(CH₂)₃NH— FAB-MS(Pos); 459(M⁺ + 1) Sal: HCl 550 11-Me-3-pyrr HO—(CH₂)₃NH— FAB-MS(Pos); 445(M⁺ + 1), Sal: HCl 551 1 iPr(EtO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos); 510(M⁺ + 1) 552 1 (S)-3-THF Me₂N—FAB-MS(Pos); 402(M⁺ + 1) 553 15 iPr (HO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos);454(M⁺ + 1), Sal: HBr 554 1 1-Me-3-pyrr (EtO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 511(M⁺ + 1) 555 1 (S)-3-THF (BnO)₂(O)P—(CH₂)₂NH—ESI-MS(Pos); 662(M⁺ + 1) 556 18 (S)-3-THF (HO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 482(M⁺ + 1) 557 15 1-Me-3-pyrr (HO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 495(M⁺ + 1), Sal: HBr 558 1 (R)-3-THF (BnO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 662(M⁺ + 1) 559 18 (R)-3-THF (HO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 482(M⁺ + 1) 560 1.23 1-Me-4-pipe 3-EtO₂C-2-thiqFAB-MS(Pos); 589(M⁺ + 1), Sal: HCl 561 1.23 1-Me-4-pipe 2-EtO₂C-1-pipeFAB-MS(Pos); 541(M⁺ + 1), Sal: HCl 562 6 1-Me-4-pipe 3-HO₂C-2-thiqFAB-MS(Pos); 561(M⁺ + 1), Sal: HCl 563 6 1-Me-4-pipe 2-HO₂C-1-pipeFAB-MS(Pos); 513(M⁺ + 1), Sal: HCl 564 1.23 (S)-1-Me-3-pyrr(S)-3-EtO₂C-2-thiq FAB-MS(Pos); 575(M⁺ + 1), Sal: HCl 565 1.23(S)-1-Me-3-pyrr (R)-3-EtO₂C-2-thiq FAB-MS(Pos); 575(M⁺ + 1), Sal: HCl566 6 (S)-1-Me-3-pyrr (S)-3-HO₂C-2-thiq FAB-MS(Pos); 547(M⁺ + 1), Sal:HCl 567 1,23 (R)-1-Me-3-pyrr (S)-3-EtO₂C-2-thiq FAB-MS(Pos); 575(M⁺ +1), Sal: HCl

TABLE 37

Ex Syn R¹ R² Data 568 1,23 (R)-1-Me-3-pyrr (R)-3-EtO₂C-2-thiqFAB-MS(Pos); 575(M⁺ + 1), Sal: HCl 569 6 (S)-1-Me-3-pyrr(R)-3-HO₂C-2-thiq FAB-MS(Pos); 547(M⁺ + 1), Sal: HCl 570 6(R)-1-Me-3-pyrr (S)-3-HO₂C-2-thiq FAB-MS(Pos); 547(M⁺ + 1), Sal: HCl 5716 (R)-1-Me-3-pyrr (R)-3-HO₂C-2-thiq FAB-MS(Pos); 547(M⁺ + 1), Sal: HCl572 1 (S)-3-THF (S)-3-EtO₂C-2-thiq FAB-MS(Pos); 562(M⁺ + 1) 573 1(S)-3-THF (R)-3-EtO₂C-2-thiq FAB-MS(Pos); 562(M⁺ + 1) 574 1 (R)-3-THF(S)-3-EtO₂C-2-thiq FAB-MS(Pos); 562(M⁺ + 1) 575 1 (R)-3-THF(R)-3-EtO₂C-2-thiq FAB-MS(Pos); 562(M⁺ + 1) 576 6 (R)-3-THF(S)-3-HO₂C-2-thiq FAB-MS(Pos); 534(M⁺ + 1) 577 6 (S)-3-THE(S)-3-HO₂C-2-thiq FAB-MS(Pos); 534(M⁺ + 1) 578 6 (R)-3-THF(R)-3-HO₂C-2-thiq FAB-MS(Pos); 534(M⁺ + 1) 579 1 3-THF H₂N— FAB-MS(Pos);374(M⁺ + 1) 580 6 (S)-3-THF (R)-3-HO₂C-2-thiq FAB-MS(Pos); 534(M⁺ + 1)581 1 sBu 3-EtO₂C-2-thiq FAB-MS(Pos); 548(M⁺ + 1) 582 1 sBu(EtO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos); 524(M⁺ + 1) 583 7 sBu(HO)₂(O)P—(CH₂)₂NH— FAB-MS(Pos); 468(M⁺ + 1) 584 4 sBu(1RS,2SR,3SR,4SR)-2,3- FAB-MS(Pos); 520(M⁺ + 1) diHO-4-HO(CH₂)₂O-cPen585 6 sBu 3-HO₂C-2-thiq FAB-MS(Pos); 520(M⁺ + 1) 586 16 iPr3-EtO₂C-2-thiq FAB-MS(Pos); 534(M⁺ + 1) 587 6 iPr 3-HO₂C-2-thiqFAB-MS(Pos); 506(M⁺ + 1) 588 1 sBu

FAB-MS(Pos); 560(M⁺ + 1) 589 1 2,2-diMe-1,3- (BnO)₂(O)P—(CH₂)₂NH—FAB-MS(Pos); 706(M⁺ + 1) dioxan-5-yl 590 1 2,2-diMe-1,3- HO—(CH₂)₃NH—FAB-MS(Pos.); 476(M⁺ + 1) dioxan-5-yl 591 22 (HO—CH₂)₂CH— HO—(CH₂)₃NH—FAB-MS(Pos.); 436(M⁺ + 1) 592 1 1-Me-4-pipe (2-HO-Ph)-NH— FAB-MS(Pos);493(M⁺ + 1)

TABLE 38

Ex Syn R¹ R² Data 593 16 AcNH(CH₂)₂— 3-EtO₂C-2-thiq FAB-MS(Pos);577(M⁺ + 1) 594 6 AcNH(CH₂)₂— 3-HO₂C-2-thiq FAB-MS(Pos); 549(M⁺ + 1) 59511 1-Me-3-pyrr (2-HO-Ph)-N— FAB-MS(Pos); 479(M⁺ + 1), Sal: HCl 596 16

(S)-EtO₂C-(CH₂)₂—CH(CO₂Et)-NH— FAB-MS(Pos); 584(M⁺ + 1) 597 6

(S)-HO₂C-(CH₂)₂—CH(CO₂H)—NH— FAB-MS(Pos); 528(M⁺ + 1)

TABLE 39

EX Syn R Data 598 1 CO₂Et ESI-MS(Neg); 431(M⁺ − 1) 599 6 CO₂HFAB-MS(Pos); 405(M⁺ + 1)

TABLE 40

Ex Syn —R¹—R²— R³ Data 600 16 —CH═CH—CH═CH— CO₂Et FAB-MS(Pos); 440(M⁺− 1) 601 6 —CH═CH—CH═CH— CO₂H FAB-MS(Pos); 412(M⁺ − 1) 602 16 —(CH₂)₄—CO₂Et FAB-MS(Pos); 444(M⁺ − 1) 603 6 —(CH₂)₄— CO₂H FAB-MS(Pos); 416(M⁺− 1) 604 16 —C(═CH₂)—(CH₂)₂— CO₂Et FAB-MS(Pos); 442(M⁺ − 1) 605 6—C(═CH₂)—(CH₂)₂— CO₂H FAB-MS(Pos); 414(M⁺ − 1) 606 16 —CH(Me)-(CH₂)₂—CO₂Et FAB-MS(Pos); 444(M⁺ − 1) 607 6 —CH(Me)-(CH₂)₂— CO₂H FAB-MS(Pos);416(M⁺ − 1) 608 16 —(CH₂)₃— CO₂Et FAB-MS(Pos); 430(M⁺ − 1) 609 6—(CH₂)₃— CO₂H FAB-MS(Pos); 402(M⁺ − 1) 610 16 —CH₂—C(═CH₂)—(CH₂)₂— CO₂EtFAB-MS(Pos); 456(M⁺ − 1) 611 6 —CH₂—C(═CH₂)—(CH₂)₂— CO₂H FAB-MS(Pos);428(M⁺ − 1) 612 16 —CH₂—CH(Me)-(CH₂)₂— CO₂Et FAB-MS(Pos); 458(M⁺ − 1)613 6 —CH₂—CH(Me)-(CH₂)₂— CO₂H FAB-MS(Pos); 430(M⁺ − 1)

TABLE 41

Ex Syn R¹ R² A R³ Data 614 16 F cPen CMe EtO₂C—CH₂— FAB-MS(Pos); 472(M⁺− 1) 615 6 F cPen CMe HO₂C—CH₂— FAB-MS(Pos); 444(M⁺ − 1) 616 1 F Et NEtO₂C—CH₂— FAB-MS(Pos.); 419(M⁺ − 1) 617 6 F Et N HO₂C—CH₂—FAB-MS(Pos.); 391(M⁺ − 1) 618 1 F Et N (EtO)₂(O)P—(CH₂)₂— FAB-MS(Pos);497(M⁺ − 1) 619 15 F Et N (HO)₂(O)P—(CH₂)₂— ESI-MS(Pos.); 441(M⁺ − 1),Sal: HBr 620 16 OEt Et N EtO₂C—CH₂— FAB-MS(Pos); 445(M⁺ − 1) 621 6 OEtEt N HO₂C—CH₂— FAB-MS(Pos.); 417(M⁺ − 1) 622 16 F cPen N EtO₂C—CH₂—FAB-MS(Pos); 459(M⁺ − 1) 623 6 F cPen N HO₂C—CH₂— FAB-MS(Pos); 431(M⁺− 1) 624 16 F (Et)₂CH— N EtO₂C—CH₂— FAB-MS(Pos); 461(M⁺ − 1) 625 6 F(Et)₂CH— N HO₂C—CH₂— FAB-MS(Pos); 433(M⁺ − 1) 626 16 F (Et)₂CH— N(EtO)₂(O)P—(CH₂)₂— FAB-MS(Pos); 539(M⁺ − 1) 627 7 F (Et)₂CH— N(HO)₂(O)P—(CH₂)₂— FAB-MS(Pos); 483(M⁺ − 1) 628 16 F (Et)₂CH— N(S)-EtO₂C— FAB-MS(Pos); 561(M⁺ − 1) (CH₂)₂CH(CO₂Et)- 629 6 F (Et)₂CH— N(S)-HO₂C— FAB-MS(Pos); 505(M⁺ − 1) (CH₂)₂CH(CO₂H)—

NMR data of some compounds in the Examples are shown below in Tables 42to 44. TABLE 42 Ex Data 6 NMR(DMSO-d₆) δ; 1.10-1.25(m, 1H), 1.27-1.50(m,4H), 1.61-1.70(m, 1H), 1.72-1.85(m, 6H), 1.85-2.01(m, 4H), 2.19-2.32(m,2H), 3.50-3.63(m, 1H), 4.05(d, J=5.4Hz, 2H), 5.12-5.22(m, 1H), 6.33(dd,J=2.0, 8.3Hz, 1H), 6.85(d, J=7.3Hz, 1H), 7.79(d, J=12.2Hz, 1H), 8.60(s,1H), 10.32(t, J=5.4Hz, 1H), 12.64(brs, 1H) 7 NMR(DMSO-d₆) δ;1.11-1.24(m, 1H), 1.27-1.48(m, 7H), 1.60-1.69(m, 1H), 1.71-1.89(m, 4H),1.92-2.00(m, 2H), 3.44-3.62(m, 3H), 4.43(q, J=7.0Hz, 2H), 6.29(d,J=6.4Hz, 1H), 6.70(d, J=7.4Hz, 1H), 7.75(d, J=12.2Hz, 1H), 8.65(s, 1H),10.16(t, J=5.9Hz, 1H) 15 NMR(DMSO-d₆) δ; 1.10-1.24(m, 1H), 1.27-1.50(m,4H), 1.60-1.70(m, 1H), 1.71-2.00(m, 12H), 2.18-2.32(m, 2H), 3.44-3.64(m,3H), 5.10-5.25(m, 1H), 6.86(d, J=7.3Hz, 1H), 7.76(d, J=12.2Hz, 1H),8.62(s, 1H), 10.14(brs, 1H) 18 NMR(DMSO-d₆) δ; 1.10-1.24(m, 1H),1.25-1.50(m, 7H), 1.51-1.56(s, 3H), 1.60-1.69(m, 1H), 1.71-2.02(m, 6H),3.40-3.57(m, 3H), 4.02(d, J=13.2Hz, 2H), 4.50(d, J=13.2Hz, 2H),4.72-4.78(m, 1H), 6.29(d, J=8.3Hz, 1H), 6.58(d, J=6.8Hz, 1H), 7.79(d,J=12.2Hz, 1H), 9.54(s, 1H), 10.14(t, J=5.8Hz, 1H) 22 NMR(DMSO-d₆) δ;1.09-1.23(m, 1H), 1.24-1.48(m, 4H), 1.59-1.68(m, 1H), 1.70-1.98(m, 6H),3.38-3.61(m, 3H), 3.75-3.92(m, 4H), 4.80-4.93(m, 1H), 5.13(brs, 2H),6.21(d, J=7.8Hz, 1H), 6.85(d, J=7.3Hz, 1H), 7.77(d, J=12.2Hz, 1H),8.69(s, 1H), 10.19(t, J=5.8Hz, 1H) 161 NMR(DMSO-d₆) δ; 1.10-1.25(m, 1H),1.27-1.49(m, 7H), 1.60-1.69(m, 1H), 1.72-1.80(m, 2H), 1.91-2.00(m, 2H),3.51-3.62(m, 1H), 4.05(d, J=5.4Hz, 2H), 4.43(q, J=6.9Hz, 2H), 6.31(dd,J=2.4, 8.3Hz, 1H), 6.71(d, J=7.4Hz, 1H), 7.77(d, J=12.2Hz, 1H), 8.65(s,1H), 10.35(t, J=5.4Hz, 1H), 12.63(brs, 1H) 255 NMR(DMSO-d₆) δ;1.10-1.25(m, 1H), 1.27-1.49(m, 4H), 1.50(d, J=6.8Hz, 6H), 1.60-1.70(m,1H), 1.71-1.80(m, 2H), 1.91-2.00(m, 2H), 3.53-3.65(m, 1H), 4.05(d,J=5.4Hz, 2H), 5.12(quintet, J=6.8Hz, 1H), 6.30(dd, J=2.5, 8.3Hz, 1H),6.87(d, J=6.9Hz, 1H), 7.80(d, J=12.2Hz, 1H), 8.65(s, 1H), 10.34(t,J=5.4Hz, 1H), 12.62(brs, 1H) 259 NMR(DMSO-d₆) δ; 1.10-1.25(m, 1H),1.23-1.48(m, 5H), 1.53-1.81(m, 8H), 1.85-1.94(m, 2H), 1.94-2.02(m, 2H),2.04-2.13(m, 2H), 3.50-3.64(m, 1H), 4.05(d, J=5.4Hz, 2H), 4.56-4.67(m,1H), 6.39(dd, J=2.0, 8.0Hz, 1H), 6.78(d, J=7.4Hz, 1H), 7.79(d, J=12.7Hz,1H), 8.64(s, 1H), 10.33(t, J=5.4Hz, 1H), 12.63(brs, 1H) 406 NMR(DMSO-d₆)δ; 1.12-1.24(m, 1H), 1.26-1.49(m.4H), 1.59-2.00(m, 13H), 2.18-2.29(m,2H), 3.36-3.48(m, 2H), 3.50-3.61(m, 1H), 3.94-4.06(m, 1H), 5.10-5.21(m,1H), 5.33(brs, 1H), 6.31(d, 1H, J=6.9Hz), 6.84(d, J=6.9Hz, 1H), 7.77(d,J=12.2Hz, 1H), 8.62(s, 1H), 10.14(t, J=5.9Hz, 1H), 12.45(brs, 1H) 416NMR(DMSO-d₆) δ; 1.10-1.24(m, 1H), 1.27-1.50(m, 4H), 1.60-1.70(m, 1H),1.71-2.00(m, 10H), 2.19-2.31(m, 2H), 3.50-3.63(m, 3H), 3.87-3.96(m, 2H),5.11-5.22(m, 1H), 6.32(d, J=6.8Hz, 1H), 6.85(d, J=7.3Hz, 1H), 7.78(d,J=12.2Hz, 1H), 8.62(s, 1H), 10.22(t, J=5.8Hz, 1H)

TABLE 43 Ex Data 417 NMR(DMSO-d₆) δ; 1.10-1.24(m, 1H), 1.27-1.50(m, 4H),1.60-1.70(m, 1H), 1.71-2.00(m, 10H), 2.18-2.33(m, 2H), 2.72-2.88(m, 2H),3.50-3.66(m, 1H), 4.75-4.82(m, 1H), 5.11-5.21(m, 1H), 6.30(brs, 1H),6.85(d, J=7.3Hz, 1H), 7.77(d, J=12.2Hz, 1H), 8.60(s, 1H), 10.59(d,J=7.8Hz, 1H) 419 NMR(DMSO-d₆, 80° C.) δ; 1.15-1.28(m, 1H), 1.30-1.50(m,4H), 1.60-1.69(m, 1H), 1.70-2.02(m, 10H), 2.15-2.30(m, 2H), 2.95-3.30(m,2H), 3.48-3.65(m, 1H), 4.05(brs, 1H), 4.49(brs, 1H), 4.60-5.10(m, 2H),5.82(brd, J=6.4Hz, 1H), 6.82(d, J=6.8Hz, 1H), 7.16(brs, 4H), 7.74(d,J=12.7Hz, 1H), 7.89(s, 1H), 12.48(brs, 1H) 425 NMR(DMSO-d₆) δ;1.10-1.25(m, 1H), 1.27-1.50(m, 4H), 1.60-1.70(m, 1H), 1.71-2.00(m, 11H),2.04-2.15(m, 1H), 2.20-2.33(m, 4H), 3.52-3.64(m, 1H), 4.48-4.56(m, 1H),5.12-5.21(m, 1H), 6.34(brd, J=6.4Hz, 1H), 6.85(d, J=6.8Hz, 1H), 7.79(d,J=12.2Hz, 1H), 8.59(s, 1H), 10.48(d, J=7.8Hz, 1H)12.50(brs, 2H) 429NMR(DMSO-d₆) δ; 1.12-1.24(m, 1H), 1.26-1.48(m, 4H), 1.60-1.68(m, 1H),1.71-1.99(m, 12H), 2.18-2.30(m, 2H), 2.88(dd, J=7.4, 13.7Hz, 1H),3.12(dd, J=5.4, 13.7Hz, 1H), 3.50-3.62(m, 1H), 4.38-4.51(m, 1H),5.10-5.18(m, 1H), 6.30(d, J=6.3Hz, 1H), 6.83(d, J=7.3Hz, 1H),7.14-7.30(m, 5H), 7.75(d, J=12.2Hz, 1H), 8.57(s, 1H), 10.18(d, J=7.8Hz,1H) 482 NMR(DMSO-d₆) δ; 0.77(t, J=7.4Hz, 6H), 1.12-1.52(m, 5H),1.61-2.00(m, 11H), 3.44-3.55(m, 2H), 3.58-3.70(m, 1H), 4.80-4.90(m, 1H),6.26(d, J=6.8H, 1H), 6.93(d, J=6.8Hz, 1H), 7.77 d, J=12.2Hz, 1H),8.51(s, 1H), 10.16(t, J=5.6Hz, 1H) 485 NMR(DMSO-d₆) δ; 0.74-0.82(m, 6H),1.11-1.52(m, 5H), 1.60-1.98(m, 10H), 2.05-2.15(m, 1H), 2.23-2.37(m, 2H),3.60-3.75(m, 1H), 4.48-4.56(m, 1H), 4.80-4.92(m, 1H), 6.30(d, J=6.8H,1H), 6.94(d, J=6.9Hz, 1H), 7.80(d, J=12.2Hz, 1H), 8.50(s, 1H), 10.51(d,J=7.8Hz, 1H), 12.49(brs, 2H) 492 NMR(DMSO-d₆) δ; 0.78(t, J=7.3Hz, 6H),1.11-1.51(m, 5H), 1.62-1.98(m, 9H), 2.75(dd, J=5.4, 16.6Hz, 1H),2.84(dd, J=5.6, 16.6Hz, 1H), 3.60-3.75(m, 1H), 4.76-4.90(m, 2H), 6.28(d,J=6.8H, 1H), 6.93(d, J=6.8Hz, 1H), 7.78(d, J=12.2Hz, 1H), 8.51(s, 1H),10.62(d, J=8.3Hz, 1H), 12.68(brs, 2H) 501 NMR(DMSO-d₆) δ; 0.78(t,J=7.3Hz, 6H), 1.10-1.50(m, 5H), 1.60-2.00(m, 9H), 3.60-3.70(m, 1H),3.80-4.05(m, 2H), 4.80-4.93(m, 1H), 6.95(d, J=6.8Hz, 1H), 7.79(d,J=12.3Hz, 1H), 8.54(s, 1H), 10.48(t, J=5.8Hz, 1H) 522 NMR(DMSO-d₆) δ;0.78(t, J=7.4Hz, 6H), 1.11-1.50(m, 5H), 1.51-2.00(m, 13H), 3.34-3.39(m,2H), 3.60-3.70(m, 1H), 4.80-4.90(m, 1H), 6.94(d, J=6.9Hz, 1H), 7.79(d,J=12.2Hz, 1H), 8.53(s, 1H), 10.16(t, J=5.6Hz, 1H) 527 NMR(DMSO-d₆, 80°C.) δ; 0.79(t, J=7.3Hz, 6H), 1.01(d, J=13.7Hz, 6H), 1.13-1.48(m, 5H),1.58-1.97(m, 9H), 3.25-3.45(m, 2H), 3.54(brs, 1H), 4.65(brs, 1H),5.70-5.84(m, 1H), 6.82(d, J=6.8Hz, 1H), 7.92(d, J=12.6Hz, 1H), 8.52(s,1H), 10.05(brs, 1H) 553 NMR(DMSO-d₆) δ; 1.10-1.25(m, 1H), 1.27-1.50(m,4H), 1.51(d, J=6.3Hz, 6H), 1.60-1.70(m, 1H), 1.71-1.80(m, 2H),1.81-1.99(m, 4H), 3.45-3.56(m, 2H), 3.56-3.66(m, 1H), 5.07-5.20(m, 1H),6.88(d, J=7.3Hz, 1H), 7.78(d, J=12.2Hz, 1H), 8.69(s, 1H), 10.15(brs, 1H)556 NMR(DMSO-d₆) δ; 1.10-1.50(m, 5H), 1.60-1.70(m, 1H), 1.70-1.90(m,4H), 1.90-2.02(m, 2H), 2.05-2.17(m, 1H), 2.55-2.67(m, 1H), 3.42-3.59(m,3H), 3.76-3.84(m, 1H), 3.88-3.96(m, 1H), 4.02-4.11(m, 1H), 4.22-4.30(m,1H), 5.45(brs, 1H), 6.34(brd, J=5.9Hz, 1H), 6.90(d, J=7.3Hz, 1H),7.76(d, J=12.2Hz, 1H), 8.65(s, 1H), 10.13(t, J=5.8Hz, 1H)

TABLE 44 Ex Data 559 NMR(DMSO-d₆) δ; 1.10-1.50(m, 5H), 1.60-1.70(m, 1H),1.70-1.90(m, 4H), 1.90-2.02(m, 2H), 2.05-2.17(m, 1H), 2.55-2.67(m, 1H),3.42-3.59(m, 3H), 3.76-3.84(m, 1H), 3.88-3.96(m, 1H), 4.02-4.11(m, 1H),4.22-4.30(m, 1H), 5.45(brs, 1H), 6.34(brd, J=6.4Hz, 1H), 6.90(d,J=7.3Hz, 1H), 7.76(d, J=12.2Hz, 1H), 8.65(s, 1H), 10.13(t, J=5.8Hz, 1H)576 NMR(DMSO-d₆, 80° C.) δ; 1.15-1.30(m, 1H), 1.30-1.50(m, 4H),1.60-1.70(m, 1H), 1.70-1.82(m, 2H), 1.94-2.03(m, 2H), 2.08-2.22(m, 1H),2.50-2.64(m, 1H), 2.90-3.35(m, 2H), 3.46-3.58(m, 1H), 3.74-3.86(m, 1H),3.89-4.00(m, 1H), 4.00-4.25(m, 3H), 4.35-5.10(m, 2H), 5.35(brs, 1H),5.86(brd, J=6.8Hz, 1H), 6.88(brd, J=6.4Hz, 1H), 7.16(brs, 4H), 7.73(d,J=12.2Hz, 1H), 7.92(s, 1H) 578 NMR(DMSO-d₆, 80° C.) δ; 1.15-1.30(m, 1H),1.30-1.50(m, 4H), 1.60-1.70(m, 1H), 1.70-1.82(m, 2H), 1.94-2.03(m, 2H),2.08-2.22(m, 1H), 2.50-2.64(m, 1H), 2.94-3.35(m, 2H), 3.46-3.58(m, 1H),3.74-3.85(m, 1H), 3.90-4.00(m, 1H), 4.00-4.25(m, 3H), 4.35-5.15(m, 2H),5.35(brs, 1H), 5.87(brd, J=6.3Hz, 1H), 6.88(brd, J=7.3Hz, 1H), 7.16(brs,4H), 7.73(d, J=12.2Hz, 1H), 7.92(s, 1H), 12.46(brs, 1H) 583 NMR(DMSO-d₆)δ; 0.84(t, J=7.4Hz, 3H), 1.12-1.46(m, 5H), 1.49(d, J=6.3Hz, 3H),1.61-1.69(m, 1H), 1.70-1.90(m, 6H), 1.91-2.00(m, 2H), 3.43-3.65(m, 3H),4.93(q, J=6.5Hz, 1H), 6.29(d, J=6.4Hz, 1H), 6.86(d, J=7.3Hz, 1H),7.70(d, J=12.2Hz, 1H), 8.58(s, 1H), 10.15(t, J=5.6Hz, 1H) 619NMR(DMSO-d₆) δ; 1.10-1.23(m, 1H), 1.29-1.50(m, 7H), 1.62-1.69(m, 1H),1.72-1.80(m, 2H), 1.80-1.90(m, 2H), 1.92-1.99(m, 2H), 3.45-3.56(m, 2H),3.60-3.70(m, 1H), 4.58(q, J=7.3Hz, 2H), 6.73(d, J=7.3Hz, 1H), 7.70(d,J=11.7Hz, 1H), 10.00(t, J=5.4Hz, 1H) 627 NMR(DMSO-d₆) δ; 0.83(t,J=7.4Hz, 6H), 1.10-1.24(m, 1H), 1.26-1.52(m, 4H), 1.55-2.02(m, 11H),3.44-3.55(m, 2H), 3.62-3.75(m, 1H), 4.94-5.04(m, 1H), 6.65(d, J=8.3Hz,1H), 6.91(d, J=6.8Hz, 1H), 7.71(d, J=11.7Hz, 1H), 10.00(t, J=5.6Hz, 1H)629 NMR(DMSO-d₆) δ; 0.70-0.77(m, 6H), 1.11-1.24(m, 1H), 1.28-1.52(m,4H), 1.63-1.70(m, 1H), 1.72-1.86(m, 4H), 1.90-2.03(m, 5H), 2.05-2.17(m,1H), 2.25-2.39(m, 2H), 3.65-3.76(m, 1H), 4.51-4.57(m, 1H), 4.98-5.07(m,1H), 6.70(d, J=8.3Hz, 1H), 6.93(d, J=6.8Hz, 1H), 7.75(d, J=11.7Hz, 1H),10.49(d, J=7.3Hz, 1H)

The structures of alternative compounds of the invention are shown belowin Tables 45 to 67. These can be produced readily by the productionprocesses described above, the processes described in the Examples orprocesses obvious to persons skilled in the art or modified processesthereof. TABLE 45

Ex R A1  (HO)₂(O)P—CF₂CH₂NH— A2  (S)-HO₂C—(CH₂)₃CH(CO₂H)NH— A3 (HO₂C—CH₂)₂CH—NH— A4  (HO₂C—(CH₂)₂)(HO₂C—CH₂)N— A5 (HO₂C—(CH₂)₃)(HO₂C—CH₂)N— A6  (HO₂C—(CH₂)₃)(HO₂C—(CH₂)₂)N— A7 (HO₂C)₂CHNH— A8  ((HO₂C—(CH₂)₂)₂N— A9  HO₂C—CH₂CH(CH₂OH)CH₂NH— A10HO₂C—(CH₂)₂—CH(CH₂OH)NH— A11 (HO₂C—CH₂)₂CHCH₂NH— A12 HO₂C—CH(OH)CH₂NH—A13 HO₂C—CH₂CH(OH)CH₂NH— A14 HO—(CH₂)₃—CH(CO₂H)NH— A15HO—CH₂CH(CO₂H)CH₂NH— A16 HO₂C—CF₂CH₂NH— A17 HO₂C—CH₂CF₂CH₂NH— A18HO₂C—CF₂—(CH₂)₂—NH— A19 HO₂C—CF₂CH₂CH(CO₂H)NH— A20HO₂C—CH₂CF₂CH(CO₂H)NH— A21 HO₂C—CF₂CH(CO₂H)NH— A222-((HO)₂(O)P)-cHex-NH— A23 3-((HO)₂(O)P)-cHex-NH— A244-((HO)₂(O)P)-1-pipe A25 (HO)₂(O)P—CHF—CH₂NH— A26 HO₂C—CHF—CH₂NH— A27HO₂C—CH₂—CHF—CH₂NH— A28 HO₂C—CHF—(CH₂)₂—NH— A29 HO₂C—CHF—CH₂CH(CO₂H)NH—A30 HO₂C—CH₂—CHF—CH(CO₂H)NH— A31 HO₂C—CHF—CH(CO₂H)NH—

TABLE 46

Ex R B1  (HO)₂(O)P—O—(CH₂)₂—NH— B2  (HO₂C—(CH₂)₂)HO₂C—CH₂)N— B3 (HO₂C—(CH₂)₃)(HO₂C—CH₂)N— B4  (HO₂C—(CH₂)₃)(HO₂C—(CH₂)₂)N— B5 (HO₂C)₂CHNH— B6  ((HO₂C—(CH₂)₂)₂N— B7  HO₂C—CH₂CH(CH₂OH)CH₂NH— B8 HO₂C—(CH₂)₂—CH(CH₂OH)NH— B9  (HO₂C—CH₂)₂CHCH₂NH— B10 HO₂C—CH(OH)CH₂NH—B11 HO₂C—CH₂CH(OH)CH₂NH— B12 HO—(CH₂)3—CH(CO₂H)NH— B13HO—CH₂CH(CO₂H)CH₂NH— B14 HO₂C—CF₂CH₂NH— B15 HO₂C—CH₂CF₂CH₂NH— B16HO₂C—CF₂—(CH₂)₂—NH— B17 HO₂C—CF₂CH₂CH(CO₂H)NH— B18HO₂C—CH₂CF₂CH(CO₂H)NH— B19 HO₂C—CF₂CH(CO₂H)NH— B202-((HO)₂(O)P)-cHex-NH— B21 3-((HO)₂(O)P)-cHex-NH— B224-((HO)₂(O)P)-1-pipe B23 (HO)₂(O)P—CHF—CH₂NH— B24 HO₂C—CHF—CH₂NH— B25HO₂C—CH₂—CHF—CH₂NH— B26 HO₂C—CHF—(CH₂)₂—NH— B27 HO₂C—CHF—CH₂CH(CO₂H)NH—B28 HO₂C—CH₂—CHF—CH(CO₂H)NH— B29 HO₂C—CHF—CH(CO₂H)NH—

TABLE 47

Ex R C1  HO₂C—CH₂NH— C2  (S)-HO₂C—(CH₂)₂CH(CO₂H)NH— C3 (HO)₂(O)P—(CH₂)₂NH— C4  (HO)₂(O)P—CF₂CH₂NH— C5  (S)-HO₂C—CH₂CH(CO₂H)NH—C6  (S)-HO₂C—(CH₂)₃CH(CO₂H)NH— C7  (HO₂C—CH₂)₂CH—NH— C8 (HO)₂(O)P—O—(CH₂)₂—NH— C9  (HO₂C—(CH₂)₂)(HO₂C—CH₂)N— C10(HO₂C—(CH₂)₃)(HO₂C—CH₂)N— C11 (HO₂C—(CH₂)₃)(HO₂C(CH₂)₂)N— C12(HO₂C)₂CHNH— C13 ((HO₂C—(CH₂)₂)2N— C14 HO₂C—CH₂CH(CH₂OH)CH₂NH— C15HO₂C—(CH₂)₂—CH(CH₂OH)NH— C16 (HO₂C—CH₂)₂CHCH₂NH— C17 HO₂C—CH(OH)CH₂NH—C18 HO₂C—CH₂CH(OH)CH₂NH— C19 HO—(CH₂)₃—CH(CO₂H)NH— C20HO—CH₂CH(CO₂H)CH₂NH— C21 HO₂C—CF₂CH₂NH— C22 HO₂C—CH₂CF₂CH₂NH— C23HO₂C—CF₂—(CH₂)₂—NH— C24 HO₂C—CF₂CH₂CH(CO₂H)NH— C25HO₂C—CH₂CF₂CH(CO₂H)NH— C26 HO₂C—CF₂CH(CO₂H)NH— C272-((HO)₂(O)P)-cHex-NH— C28 3-((HO)₂(O)P)-cHex-NH— C294-((HO)₂(O)P)-1-pipe C30 (HO)₂(O)P—CHF—CH₂NH— C31 HO₂C—CHF—CH₂NH— C32HO₂C—CH₂—CHF—CH₂NH— C33 HO₂C—CHF—(CH₂)₂—NH— C34 HO₂C—CHF—CH₂CH(CO₂H)NH—C35 HO₂C—CH₂—CHF—CH(CO₂H)NH— C36 HO₂C—CHF—CH(CO₂H)NH—

TABLE 48

Ex R D1  (S)-HO₂C—(CH₂)₂CH(CO₂H)NH— D2  (HO)₂(O)P—(CH₂)₂NH— D3 (HO)₂(O)P—CF₂CH₂NH— D4  (S)-HO₂C—CH₂CH(CO₂H)NH— D5 (S)-HO₂C—(CH₂)₃CH(CO₂H)NH— D6  (HO₂C—CH₂)₂CH—NH— D7 (HO)₂(O)P—O—(CH₂)₂—NH— D8  (HO₂C—(CH₂)₂)(HO₂C—CH₂)N— D9 (HO₂C—(CH₂)₃)(HO₂C—CH₂)N— D10 (HO₂C—(CH₂)₃)(HO₂C—(CH₂)₂)N— D11(HO₂C)₂CHNH— D12 ((HO₂C—(CH₂)₂)₂N— D13 HO₂C—CH₂CH(CH₂OH)CH₂NH— D14HO₂C—(CH₂)₂—CH(CH₂OH)NH— D15 (HO₂C—CH₂)₂CHCH₂NH— D16 HO₂C—CH(OH)CH₂NH—D17 HO₂C—CH₂CH(OH)CH₂NH— D18 HO—(CH₂)₃—CH(CO₂H)NH— D19HO—CH₂CH(CO₂H)CH₂NH— D20 HO₂C—CF₂CH₂NH— D21 HO₂C—CH₂CF₂CH₂NH— D22HO₂C—CF₂—(CH₂)₂—NH— D23 HO₂C—CF₂CH₂CH(CO₂H)NH— D24HO₂C—CH₂CF₂CH(CO₂H)NH— D25 HO₂C—CF₂CH(CO₂H)NH— D262-((HO)₂(O)P)-cHex-NH— D27 3-((HO)₂(O)P)-cHex-NH— D284-((HO)₂(O)P)-1-pipe D29 (HO)₂(O)P—CHF—CH₂NH— D30 HO₂C—CHF—CH₂NH— D31HO₂C—CH₂—CHF—CH₂NH— D32 HO₂C—CHF—(CH₂)₂—NH— D33 HO₂C—CHF—CH₂CH(CO₂H)NH—D34 HO₂C—CH₂—CHF—CH(CO₂H)NH— D35 HO₂C—CHF—CH(CO₂H)NH—

TABLE 49

Ex R¹ R¹ E1  3,4-diMe-cPen H E2  3-Me-cPen H E3 3,4-diMe-cyclopent-3-en-1-yl H E4  3,3-diMe-cPen H E5  3,4-diF-cPen HE6  3-F-cPen H E7  3,3-diF-cPen H E8  3,4-diF-cyclopent-3-en-1-yl H E9 3-F-cyclopent-3-en-1-yl H E10 3-THP H E11 2-Py H E12 3-Py H E13 4-Py HE14 —CH(Et)-(CH₂)₃— E15 —CH(Et)-(CH₂)₂— E16 —CH₂—C(Me)₂-(CH₂)₂— E17—CH₂—CHF—CH₂2 E18 —CH₂—CF₂—CH₂2 E19 (Et)₂CH— Cl E20 cPen Cl E21 (Et)₂CH—CF₃ E22 cPen CF₃

TABLE 50

Ex R¹ R² F1  FH₂C—CH(Me)- H F2  F₂HC—CH(Me)- H F3  iPr H F4 (HO—CH₂)₂CH— H F5  1-Me-3-pyrr H F6  3-THF H F7 2,2-diMe-1,3-dioxan-5-yl H F8  2,2-diEt-1,3-dioxan-5-yl H F9 3,4-diMe-cPen H F10 3-Me-cPen H E11 3,4-diMe-cyclopent-3-en-1-yl H F123-Me-cyclopent-3-en-1-yl H F13 3,3-diMe-cPen H F14 3,4-diF-cPen H F153-F-cPen H F16 3,3-diF-cPen H F17 3,4-diF-cyclopent-3-en-1-yl H F183-F-cyclopent-3-en-1-yl H F19 3-THP H F20 2-Py H E21 3-Py H F22 4-Py HF23 —CH(Et)-(CH₂)₃— F24 —CH(Et)-(CH₂)₂— F25 —CH₂—C(═CH₂)—(CH₂)₂— F26—CH₂—CH(Me)-(CH₂)₂— F27 —CH₂—C(Me)₂-(CH₂)₂— F28 —CH₂—CHF—(CH₂)₂— F29—CH₂—CF₂—CH₂2 F30 (Et)₂CH— Cl F31 cPen Cl F32 (Et)₂CH— CF₃ F33 cPen CF₃

TABLE 51

Ex R¹ R² G1  FH₂C—CH(Me)- H G2  F₂HC—CH(Me)- H G3  iPr H G4  Et H G5 (HO—CH₂)₂CH— H G6  1-Me-3-pyrr H G7  3-Tiff H G8 2,2-diMe-1,3-dioxan-5-yl H G9  2,2-diEt-1,3-dioxan-5-yl H G103,4-diMe-cPen H G11 3-Me-cPen H G12 3,4-diMe-cyclopent-3-en-1-yl H G133-Me-cyclopent-3-en-1-yl H G14 3,3-diMe-cPen H G15 3,4-diF-cPen H G163-F-cPen H G17 3,3-diF-cPen H G18 3,4-diF-cyclopent-3-en-1-yl H G193-F-cyclopent-3-en-1-yl H G20 3-THP H G21 2-Py H G22 3-Py H G23 4-Py HG24 —CH(Et)-(CH₂)₃— G25 —CH(Et)-(CH₂)₂— G26 —CH₂—C(═CH₂)—(CH₂)₂— G27—CH₂—CH(Me)-(CH₂)₂— G28 —CH₂—C(Me)₂-(CH₂)₂— G29 —CH₂—CHF—(CH₂)₂ G30—CH₂—CF₂—(CH₂)₂ G31 (Et)₂CH— Cl G32 cPen Cl G33 (Et)₂CH— CF₃ G34 cPenCF₃

TABLE 52

Ex R¹ R² H1  FH₂C—CH(Me)- H H2  F₂HC—CH(Me)- H H3  iPr H H4  Et H H5 (HO—CH₂)₂CH— H H6  1-Me-3-pyrr H H7  3-THF H H8 2,2-diMe-1,3-dioxan-5-yl H H9  2,2-diEt-1,3-dioxan-5-yl H H103,4-diMe-cPen H H11 3-Me-cPen H H12 3,4-diMe-cyclopent-3-en-1-yl H H133-Me-cyclopent-3-en-1-yl H H14 3,3-diMe-cPen H H15 3,4-diF-cPen H H163-F-cPen H H17 3,3-diF-cPen H H18 3,4-diF-cyclopent-3-en-1-yl H H193-F-cyclopent-3-en-1-yl H H20 3-THP H H21 2-Py H H22 3-Py H H23 4-Py HH24 —CH(Et)-(CH₂)₃— H25 —CH(Et)-(CH₂)₂— H26 —CH₂—C(═CH₂)—(CH₂)₂— H27—CH₂—CH(Me)—(CH₂)₂— H28 —CH₂—C(Me)₂-(CH₂)₂— H29 —CH₂—CHF—(CH₂)₂— H30—CH₂—CF2—(CH₂)₂— H31 (Et)₂CH— Cl H32 cPen Cl H33 (Et)₂CH— CF₃ H34 cPenCF₃

TABLE 53

Ex R¹ R² I1  FH₂C—CH(Me)- H I2  F₂HC—CH(Me)- H I3  3,4-diMe-cPen H I4 3-Me-cPen H I5  3,4-diMe-cyclopent-3-en-1-yl H I6 3-Me-cyclopent-3-en-1-yl H I7  3,3-diMe-cPen H I8 2,2-diEt-1,3-dioxan-5-yl H I9  3,4-diF-cPen H I10 3-F-cPen H I113,3-diF-cPen H I12 3,4-diF-cyclopent-3-en-1-yl H I133-F-cyclopent-3-en-1-yl H I14 3-THP H I15 2-Py H I16 3-Py H I17 4-Py HI18 —CH(Et)-(CH₂)₃— I19 —CH(Et)-(CH₂)₂— I20 —CH₂—C(═CH₂)—(CH₂)₂— I21—CH₂—CH(Me)-(CH₂)₂— I22 —CH₂—C(Me)₂-(CH₂)₂— I23 —CH₂—CHF—(CH₂)₂— I24—CH₂—CF₂—(CH₂)₂— I25 (Et)₂CH— Cl I26 cPen Cl I27 (Et)₂CH— CF₃ I28 cPenCF₃

TABLE 54

Ex R¹ R² J1  FH₂C—CH(Me)- H J2  F₂HC—CH(Me)- H J3  iPr H J4  Et H J5 (HO—CH₂)₂CH— H J6  1-Me-3-pyrr H J7  3-THF H J8 2,2-diMe-1,3-dioxan-5-yl H J9  2,2-diEt-1,3-dioxan-5-yl H J103,4-diMe-cPen H J11 3-Me-cPen H J12 3,4-diMe-cyclopent-3-en-1-yl H J133-Me-cyclopent-3-en-1-yl H J14 3,3-diMe-cPen H J15 3,4-diF-cPen H J163-F-cPen H J17 3,3-diF-cPen H J18 3,4-diF-cyclopent-3-en-1-yl H J193-F-cyclopent-3-en-1-yl H J20 3-THP H J21 2-Py H J22 3-Py H J23 4-Py HJ24 —CH(Et)-(CH₂)₃— J24 —CH(Et)-(CH₂)₂— J25 —CH₂—C(═CH₂)—(CH₂)₂— J26—CH₂—CH(Me)-(CH₂)₂— J27 —CH₂—C(Me)₂-(CH₂)₂— J28 —CH₂—CHF—(CH₂)₂— J29—CH₂—CF₂—(CH₂)₂— J30 (Et)₂CH— Cl J31 cPen Cl J32 (Et)₂CH— CF₃ J33 cPenCF₃

TABLE 55

Ex R¹ R² K1  FH₂C—CH(Me)- H K2  F₂HC—CH(Me)- H K3  iPr H K4  Et H K5 (HO—CH₂)₂CH— H K6  1-Me-3-pyrr H K7  3-THF H K8 2,2-diMe-1,3-dioxan-5-yl H K9  2,2-diEt-1,3-dioxan-5-yl H K103,4-diMe-cPen H K11 3-Me-cPen H K12 3,4-diMe-cyclopent-3-en-1-yl H K133-Me-cyclopent-3-en-1-yl H K14 3,3-diMe-cPen H K15 3,4-diF-cPen H K163-F-cPen H K17 3,3-diF-cPen H K18 3,4-diF-cyclopent-3-en-1-yl H K193-F-cyclopent-3-en-1-yl H K20 3-THP H K21 2-Py H K22 3-Py H K23 4-Py HK24 —CH(Et)-(CH₂)₃— K25 —CH(Et)-(CH₂)₂— K26 —CH₂—C(═CH₂)—(CH₂)₂— K27—CH₂—CH(Me)-(CH₂)₂— K28 —CH₂—C(Me)₂-(CH₂)₂— K29 —CH₂—CHF—(CH₂)₂— K30—CH₂—CF₂—(CH₂)₂— K31 (Et)₂CH— Cl K32 cPen Cl K33 (Et)₂CH— CF₃ K34 cPenCF₃

TABLE 56

Ex R¹ R² L1  FH₂C—CH(Me)- H L2  F₂HC—CH(Me)- H L3  iPr H L4  Et H L5 (HO—CH₂)_(2CH—) H L6  1-Me-3-pyrr H L7  3-THF H L8 2,2-diMe-1,3-dioxan-5-yl H L9  2,2-diEt-1,3-dioxan-5-yl H L103,4-diMe-cPen H L11 3-Me-cPen H L12 3,4-diMe-cyclopent-3-en-1-yl H L133-Me-cyclopent-3-en-1-yl H L14 3,3-diMe-cPen H L15 3,4-diF-cPen H L163-F-cPen H L17 3,3-diF-cPen H L18 3,4-diF-cyclopent-3-en-1-yl H L193-F-cyclopent-3-en-1-yl H L20 3-THP H L21 2-Py H L22 3-Py H L23 4-Py HL24 —CH(Et)-(CH₂)₃— L25 —CH(Et)-(CH₂)₂— L26 —CH₂—C(═CH₂)—(CH₂)₂— L27—CH₂—CH(Me)-(CH₂)₂— L28 —CH₂—C(Me)₂-(CH₂)₂— L29 —CH₂—CHF—(CH₂)₂— L30—CH₂—CF₂—(CH₂)₂— L31 (Et)₂CH— Cl L32 cPen Cl L33 (Et)₂CH— CF₃ L34 cPenCF₃

TABLE 57

Ex R M1  Cl M2  Br M3  Me M4  NC— M5  CF₃ M6  HO— M7  H₂N— M8  4-mor M9 1-pipe M10 Me₂N— M11 Et₂N— M12 AcN(Me)- M13 AcNH—

TABLE 58

Ex R O1 Cl O2 Br O3 Me O4 NC— O5 CF₃ O6 H2N— O7 4-mor O8 1-pipe O9 Et₂N— O10 AcN(Me)-  O11 AcNH—

TABLE 59

Ex R P1 Cl P2 Br P3 Me P4 NC— P5 CF₃ P6 HO— P7 H₂N— P8 4-mor P9 1-pipe P10 Me₂N—  P11 Et₂N—  P12 AcN(Me)-  P13 AcNH—

TABLE 60

Ex R Q1 Cl Q2 Br Q3 Me Q4 NC— Q5 CF₃ Q6 HO— Q7 H₂N— Q8 4-mor Q9 1-pipe Q10 Me₂N—  Q11 Et₂N—  Q12 AcN(Me)-  Q13 AcNH—

TABLE 61

Ex R R1 Cl R2 Br R3 Me R4 NC— R5 CF₃ R6 HO— R7 H₂N— R8 4-mor R9 1-pipe R10 Me₂N—  R11 Et₂N—  R12 AcN(Me)-  R13 AcNH—

TABLE 62

Ex R S1 Cl S2 Br S3 Me S4 NC— S5 CF₃ S6 HO— S7 H₂N— S8 4-mor S9 1-pipe S10 Me₂N—  S11 Et₂N—  S12 AcN(Me)-  S13 AcNH—

TABLE 63

Ex R T1 Cl T2 Br T3 Me T4 NC— T5 CF₃ T6 HO— T7 H₂N— T8 4-mor T9 1-pipe T10 Me₂N—  T11 Et₂N—  T12 AcN(Me)-  T13 AcNH—

TABLE 64

Ex R U1 Cl U2 Br U3 Me U4 NC— U5 CF₃ U6 HO— U7 H₂N— U8 4-mor U9 1-pipe U10 Me₂N—  U11 Et₂N—  U12 AcN(Me)-  U13 AcNH—

TABLE 65

Ex R¹ R² R³ V1  4-F-cHex cPen HO₂C—CH₂NH— V2  4-F-cHex cPen(S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V3  4-F-cHex cPen (HO)₂(O)P—(CH₂)₂NH— V4 4-F-cHex cPen (HO)₂(O)P—CF₂CH₂NH— V5  4-F-cHex (Et)₂CH— HO₂C—CH₂NH— V6 4-F-cHex (Et)₂CH— (S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V7  4-F-cHex (Et)₂CH—(HO)₂(O)P—(CH₂)₂NH— V8  4-F-cHex (Et)₂CH— (HO)₂(O)P—CF₂CH₂NH— V9 4,4-diF-cHex cPen (S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V10 4,4-diF-cHex cPen(HO)₂(O)P—(CH₂)₂NH— V11 4,4-diF-cHex cPen (HO)₂(O)P—CF₂CH₂NH— V124,4-diF-cHex (Et)₂CH— HO₂C—CH₂NH— V13 4,4-diF-cHex (Et)₂CH—(S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V14 4,4-diF-cHex (Et)₂CH— (HO)₂(O)P—(CH₂)₂NH—V15 4,4-diF-cHex (Et)₂CH— (HO)₂(O)P—CF₂CH₂NH— V16 3-THP cPen(S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V17 3-THP cPen (HO)₂(O)P—(CH₂)₂NH— V18 3-THPcPen (HO)₂(O)P—CF₂CH₂NH— V19 3-THP (Et)₂CH— HO₂C—CH₂NH— V20 3-THP(Et)₂CH— (S)-HO₂C—(CH₂)₂CH(CO₂H)NH— V21 3-THP (Et)₂CH—(HO)₂(O)P—(CH₂)₂NH— V22 3-THP (Et)₂CH— (HO)₂(O)P—CF₂CH₂NH—

TABLE 66

Ex R¹ R² R³ W1  4-F-cHex cPen HO₂C—CH₂NH— W2  4-F-cHex cPen(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W3  4-F-cHex cPen (HO)₂(O)P—(CH₂)₂NH— W4 4-F-cHex cPen (HO)₂(O)P—CF₂CH₂NH— W5  4-F-cHex (Et)₂CH— HO₂C—CH₂NH— W6 4-F-cHex (Et)₂CH— (S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W7  4-F-cHex (Et)₂CH—(HO)₂(O)P—(CH₂)₂NH— W8  4-F-cHex (Et)₂CH— (HO)₂(O)P—CF₂CH₂NH— W9 4,4-diF-cHex cPen HO₂C—CH₂NH— W10 4,4-diF-cHex cPen(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W11 4,4-diF-cHex cPen (HO)₂(O)P—(CH₂)₂NH— W124,4-diF-cHex cPen (HO)₂(O)P—CF₂CH₂NH— W13 4,4-diF-cHex (Et)₂CH—HO₂C—CH₂NH— W14 4,4-diF-cHex (Et)₂CH— (S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W154,4-diF-cHex (Et)₂CH— (HO)₂(O)P—(CH₂)₂NH— W16 4,4-diF-cHex (Et)₂CH—(HO)₂(O)P—CF₂CH₂NH— W17 3-THP cPen (S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W18 3-THPcPen (HO)₂(O)P—(CH₂)₂NH— W19 3-THP cPen (HO)₂(O)P—CF₂CH₂NH— W20 3-THP(Et)₂CH— HO₂C—CH₂NH— W21 3-THP (Et)₂CH— (S)—HO₂C—(CH₂)₂CH(CO₂H)NH— W223-THP (Et)₂CH— (HO)₂(O)P—(CH₂)₂NH— W23 3-THP (Et)₂CH—(HO)₂(O)P—CF₂CH₂NH—

TABLE 67

Ex R¹ R² R³ X1  H Et (S)—HO₂C—(CH₂)₂CH(CO₂H)NH— X2  H Et(HO)₂(O)P—CF₂CH₂NH— X3  H (Et)₂CH— (HO)₂(O)P—CF₂CH₂NH— X4  H c-Pen(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— X5  H c-Pen (HO)₂(O)P—(CH₂)₂NH— X6  H c-Pen(HO)₂(O)P—CF₂CH₂NH— X7  F Et HO₂C—CH₂NH— X8  F Et(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— X9  F Et (HO)₂(O)P—(CH₂)₂NH— X10 F Et(HO)₂(O)P—CF₂CH₂NH— X11 F (Et)₂CH— HO₂C—CH₂NH— X12 F (Et)₂CH—(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— X13 F (Et)₂CH— (HO)₂(O)P—(CH₂)₂NH— X14 F(Et)₂CH— (HO)₂(O)P—CF₂CH₂NH— X15 F c-Pen HO₂C—CH₂NH— X16 F c-Pen(S)—HO₂C—(CH₂)₂CH(CO₂H)NH— X17 F c-Pen (HO)₂(O)P—(CH₂)₂NH— X18 F c-Pen(HO)₂(O)P—CF₂CH₂NH—

1. A platelet aggregation inhibitor comprising a quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:

[the symbols in the formula have the following meanings: X: C—R⁷ or N; Y: C—R⁶ or N; R¹¹: —H, a lower alkyl which may be substituted, or an amino which may be substituted with a lower alkyl which may be substituted; R¹²: —H, or a lower alkyl or an aryl which respectively may be substituted, provided that R¹¹ and R¹² together with the adjacent nitrogen may form a cyclic amino which may be substituted; R²: a lower alkyl, a cycloalkyl, an aryl or a hetero ring, which respectively may be substituted; R³: a halogen, a lower alkyl or —O-lower alkyl; R⁴: a cycloalkyl or a non-aromatic hetero ring, which respectively may be substituted, or a lower alkyl substituted with a cycloalkyl; provided that when R⁴ represents a non-aromatic hetero ring which may be substituted, a carbon atom constituting the ring binds to the adjacent NH; R⁵: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N(lower alkyl)CO-lower alkyl, an amino which may be substituted with a lower alkyl, or a cyclic amino which may be substituted; R⁶: —H, a halogen, a lower alkyl or a halogeno-lower alkyl; R⁷: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl); provided that when Y represents C—R⁶, R² and R⁶ together may form a lower alkylene or a lower alkenylene.
 2. A P2Y12 inhibitor comprising the compound according to claim 1 as an active ingredient.
 3. Use of the compound according to claim 1 as a platelet aggregation inhibitor.
 4. Use of the compound according to claim 1 as a P2Y12 inhibitor.
 5. Use of the compound according to claim 1 for the manufacture of as a platelet aggregation inhibitor.
 6. Use of the compound according to claim 1 for the manufacture of a P2Y12 inhibitor.
 7. A quinolone derivative represented by the formula (I-a) or a pharmaceutically acceptable salt thereof:

[the symbols in the formula have the following meanings: X: C—R⁷ or N; Y: C—R⁶ or N; R¹¹: —H, a lower alkyl which may be substituted, or an amino which may be substituted with a lower alkyl which may be substituted; R¹²: —H, or a lower alkyl or an aryl, which respectively may be substituted, provided that R¹¹ and R¹² together with the adjacent nitrogen may form a cyclic amino which may be substituted; R²: a lower alkyl, a cycloalkyl, an aryl or a hetero ring, which respectively may be substituted; R³: a halogen, a lower alkyl or —O-lower alkyl; R⁴: a cycloalkyl or a non-aromatic hetero ring, which respectively may be substituted, or a lower alkyl substituted with a cycloalkyl; provided that wherein R⁴ represents a non-aromatic hetero ring which may be substituted, a carbon atom constituting the ring binds to the adjacent NH; R⁵: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N(lower alkyl)CO-lower alkyl, an amino which may be substituted with a lower alkyl, or a cyclic amino which may be substituted; R⁶: —H, a halogen, a lower alkyl or a halogeno-lower alkyl; R⁷: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl); provided that when Y represents C—R⁶, R² and R⁶ together may form a lower alkylene or a lower alkenylene and provided that 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide is excluded.
 8. The compound according to claim 7, wherein X is CH.
 9. The compound according to claim 8, wherein R³ is a halogen.
 10. The compound according to claim 9, wherein R⁴ is a cycloalkyl.
 11. The compound according to claim 10, wherein R⁵ is —H, —OH or a halogen.
 12. The compound according to claim 11, wherein R¹² is a lower alkyl respectively substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P): Group P: —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂; and Group Q: —F, —OH, —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂.
 13. The compound according to claim 11, wherein NR¹¹R¹² together is a cyclic amino group substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P). Group P: —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂; and Group Q: —F, —OH, —CO₂H, —SO₃H, —P(O)(OH)₂, and —OP(O)(OH)₂.
 14. The compound according to claim 7, which is [2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)butanedioic acid, 2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl dihydrogen phosphate, (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic acid, {2-[({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3 S)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid, {2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3R)-tetrahydrofuran-3-yl]-1,4-dihhydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid, [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-1,1-difluoroethyl]phosphonic acid, {2-[({7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino)ethyl}phosphonic acid, [2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic acid, (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)pentanedioic acid or [2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, or a pharmaceutically acceptable salt thereof.
 15. The pharmaceutical composition comprising a compound according to any one of claims 7 through 14 and a pharmaceutically acceptable carrier.
 16. The pharmaceutical composition according to claim 15, which is a platelet aggregation inhibitor.
 17. The pharmaceutical composition according to claim 15, which is a P2Y12 inhibitor.
 18. Use of the compound according to any one of claims 7 through 14 as a platelet aggregation inhibitor.
 19. Use of the compound according to any one of claims 7 through 14 as a P2Y12 inhibitor.
 20. Use of the compound according to any one of claims 7 through 14 for the manufacture of a platelet aggregation inhibitor.
 21. Use of the compound according to any one of claims 7 through 14 for the manufacture of a P2Y12 inhibitor. 